@article {pmid42627738,
year = {2026},
author = {Chang, Y and Kim, HJ and Kim, Y and Park, A and Nam, S and Banerjee, DR and Hasenour, CM and Young, JD and Brooks, GA and Wolfe, RR and Kim, IY},
title = {Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.},
journal = {American journal of physiology. Cell physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpcell.00268.2026},
pmid = {42627738},
issn = {1522-1563},
support = {2021R1A2C3005801//National Research Foundation of Korea (NRF)/ ; GCU-202106260001//Gachon University/ ; //Myocare Inc/ ; },
abstract = {A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As the glucose utilization declines in AD patients, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (A(?)) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under A(?)-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of AD patients. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by A(?) aggregates. Using a [13]C stable isotope tracer, we verified cellular lactate uptake and its incorporation into TCA cycle in neurons under the neurotoxic condition. [13]C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.},
}

@article {pmid42628381,
year = {2026},
author = {Quan, YS and Liu, JY and Liu, H and Sun, YX and Wang, YL and Liu, Z and Quan, ZS and Shen, QK},
title = {Design synthesis and evaluation of usnic acid derivatives as multi-target drugs for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110398},
doi = {10.1016/j.bioorg.2026.110398},
pmid = {42628381},
issn = {1090-2120},
abstract = {The pathogenesis of AD is complex, and existing clinical drugs only alleviate symptoms and are difficult to block the course of the disease. Although UA has neuroprotective activities such as antioxidant and anti-inflammatory properties, its anti-AD activity is severely restricted by drug defects such as a single target and insufficient blood-brain barrier permeability. Therefore, this study takes UA as the lead compound, designs and synthesizes 38 UA derivatives, systematically evaluates their anti-AD biological activity, and aims to screen for multifunctional anti AD lead compounds. Among them, the lead compound S12 exhibited exceptional activity, with an EC50 value of 1.24 μM representing a 17.9-fold improvement in potency relative to the parent compound. Furthermore, WB assays were conducted to elucidate the underlying mechanism of action of this compound. The results revealed that compound S12 exerts anti-AD activity through the synergistic modulation of multiple signaling pathways: it inhibits activation of the MAPK and NF-κB pathways, as well as aberrant phosphorylation of tau protein; concurrently, it downregulates BACE1 expression to reduce Aβ production, and suppresses activation of the Bax/Bcl-2 pathway thereby inhibiting caspase-1 activation and ultimately confers neuroprotective, anti-AD effects. The apparent permeability coefficient of compound S12 across an in vitro (BBB) model was determined to be 7.66 × 10[-6] cm/s, confirming its ability to effectively cross the BBB. Further pharmacological evaluation demonstrated that S12 exerted a potent ameliorative effect on learning and memory deficits in an AD mouse model. In vivo toxicity assessment, no gross or histopathological abnormalities were observed in the major organs, including the heart, liver, spleen, and kidneys. Moreover, S12 significantly attenuated neuronal pathological injury in the hippocampus of Aβ-induced AD model mice, underscoring its robust neuroprotective activity. In conclusion, compound S12 demonstrates robust efficacy in ameliorating learning and memory deficits, enhancing blood-brain barrier permeability, and exerting anti-AD activity. Accordingly, it represents a highly promising multifunctional therapeutic candidate for the treatment of AD.},
}

@article {pmid42630070,
year = {2026},
author = {Alsharayri, S and Knox, S and Cutty, M and Mollalo, A},
title = {Dual eligibility and neuropsychiatric symptoms and treatment disparities among Medicare Part D beneficiaries with Alzheimer's disease and related dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478140},
doi = {10.1177/13872877261478140},
pmid = {42630070},
issn = {1875-8908},
abstract = {BackgroundNeuropsychiatric symptoms (NPS) are common and clinically consequential in Alzheimer's disease and related dementias (ADRD), yet their recognition and treatment may vary across socioeconomic groups. Dual-eligible Medicare-Medicaid beneficiaries represent a vulnerable population, but differences in NPS documentation and management remain unclear.ObjectiveTo examine whether dual eligibility is associated with differences in (1) documented NPS and (2) prescription fills among Medicare beneficiaries with ADRD who received home health (HH) care.MethodsWe conducted a cross-sectional study of 167,484 Medicare Part D beneficiaries with ADRD who received HH care and were identified using the Chronic Conditions Warehouse flag. Dual eligibility was the primary exposure. NPS were identified using diagnosis codes from medical claims. Prescription fills for NPS-related medications were identified using Medicare Part D prescription drug event data (≥2 prescription fills for anxiety-related medications and antidepressants). Logistic regression models estimated associations of dual eligibility with NPS documentation and prescription fills, adjusting for demographic characteristics, original Medicare entitlement, and comorbidity burden.ResultsDual-eligible beneficiaries comprised 30.7% of the cohort. Documented confusion and anxiety were the most prevalent symptoms. Dual-eligible beneficiaries had a higher prevalence of confusion (83.5% versus 82.0%) and anxiety (57.0% versus 53.2%) compared with Medicare-only beneficiaries. After adjustment, dual eligibility was associated with higher odds of documented confusion (aOR 1.18, 95% CI 1.14-1.22) and anxiety (aOR 1.19, 95% CI 1.15-1.22). Dual eligibility was also associated with slightly higher odds of anxiety-related prescription fills (aOR 1.21, 95% CI 1.17-1.26), whereas antidepressant prescription fills did not differ (aOR 1.00, 95% CI 0.95-1.05).ConclusionsDual eligibility was associated with modest differences in NPS documentation and prescription fills, suggesting differences in recognition and management of NPS among beneficiaries with ADRD.},
}

@article {pmid42630294,
year = {2026},
author = {Shafi, S and Ansari, GA},
title = {Developing artificial intelligence-based techniques for brain MRI image segmentation.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1894751},
pmid = {42630294},
issn = {1662-4548},
abstract = {INTRODUCTION: Brain MRI image segmentation is essential for the accurate diagnosis and treatment of neurological disorders, including brain tumors, Alzheimer's disease, and multiple sclerosis. Artificial intelligence (AI), particularly deep learning, has emerged as an effective approach for improving the precision and efficiency of medical image segmentation while reducing manual effort.

METHODS: This study utilized a publicly available Kaggle brain MRI dataset containing labeled images for supervised learning. A Convolutional Neural Network (CNN)-based framework was developed for automatic brain MRI segmentation. The methodology incorporated preprocessing techniques, including noise removal, normalization, and data augmentation, to improve image quality and model performance. The proposed model was evaluated using Accuracy, Dice Score, and Intersection over Union (IoU).

RESULTS: Experimental results demonstrated that the proposed AI-based segmentation framework achieved high segmentation accuracy and effectively distinguished normal brain tissue from abnormal regions. The model outperformed conventional image-processing methods by providing improved segmentation precision, reducing manual intervention, and enhancing the reliability of medical image analysis.

DISCUSSION: The findings demonstrate the potential of AI-based deep learning techniques for automated brain MRI segmentation in clinical applications. The proposed framework can support clinicians by improving diagnostic accuracy and reducing processing time. Future work will focus on implementing more advanced deep learning architectures and expanding the dataset to further improve segmentation performance and clinical applicability.},
}

@article {pmid42631247,
year = {2026},
author = {Chen, X and Boey, J and Wei, K and Ding, C and Malagón, P and Hong, JP and Zhou, Z},
title = {The Use of Dynamic Neck Lymphaticovenous Anastomosis in the Adjunctive Treatment of Alzheimer's Disease: A Retrospective Case Series.},
journal = {Archives of plastic surgery},
volume = {53},
number = {4},
pages = {352-360},
pmid = {42631247},
issn = {2234-6163},
abstract = {BACKGROUND: Lymphovenous anastomosis (LVA) has recently emerged as a potential method for the symptomatic management of Alzheimer's disease (AD). Building on this, we conceptualize the "dynamic neck lymphovenous anastomosis" (DN-LVA) to illustrate the versatility of our technique. DN-LVA utilizes a vein graft that traverses through the sternocleidomastoid muscle to facilitate the drainage of lymphatic fluid from the deep cervical lymphatic vessels to the external jugular vein.

METHODS: This study presents a retrospective analysis of patients who underwent DN-LVA between November 2024 and January 2025. The clinical outcome was evaluated through positron emission tomography/computed tomography (PET/CT) imaging and cognitive assessment tools, which included Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR). The vein graft was harvested from the lower limb.

RESULTS: Five subjects were recruited into this study. Postoperative PET/CT scans revealed up to a 6.9% increase in glucose metabolism in patient 3, a decrease of 12.3% in amyloid deposits, and a 4.7% reduction in tau deposits in patient 5 and patient 4, respectively. Clinically, MMSE and MoCA scores were improved by 1.8 and 1.4, respectively. NPI scores decreased by 5.8 across five overall, and the CDR remained unchanged in all subjects. All grafts demonstrated vessel patency, and no postoperative complications were observed.

CONCLUSION: DN-LVA appears to be a safe, minimally invasive procedure with potential cognitive and metabolic benefits in AD. Further studies with larger cohorts and longer follow-up are warranted to confirm these preliminary findings.},
}

@article {pmid42631306,
year = {2026},
author = {de Oliveira, GLDS and Bertollo, AG},
title = {Non-pharmacological strategies for the management of Alzheimer's disease.},
journal = {Dementia & neuropsychologia},
volume = {20},
number = {},
pages = {e20250290},
pmid = {42631306},
issn = {1980-5764},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease affecting various cognitive domains, requiring a holistic and integrated therapeutic approach. The treatment of AD goes beyond pharmacological interventions, also necessitating non-pharmacological therapies that can act synergistically, both with each other and with emerging pharmacological treatments, including new anti-amyloid therapies. These therapies aim to improve patients' quality of life and alleviate behavioral symptoms, such as agitation and depression, and delay disease progression. Current clinical and meta-analytic evidence suggests that these approaches can be effectively integrated with conventional treatment, offering a valuable alternative to enhance patients' overall well-being. However, further research is needed to deepen the understanding of the ideal combination of the new anti-amyloid therapies, to address the limitations of current evidence, and to robustly establish their effectiveness in the clinical context of AD, aiming to generate a broader and more lasting impact on disease treatment. This narrative review aims to synthesize the evidence on diverse non-pharmacological therapies for managing AD and discuss their practical implications for clinical care.},
}

@article {pmid42631411,
year = {2026},
author = {Elwakil, BH and Helal, AM and El-Khatib, M and Abdelnaser, A and Darwish, AA and Shehata, NS and Akl, SH and Moneer, EA and Bakr, BA and El Wakil, A},
title = {Multilayered Silica-Core/Chitosan-Coated Nanostructures Co-Delivering Tamoxifen and Quercetin Mitigate LPS-Associated Neurodegenerative and Alzheimer's Disease-Like Alterations.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {114},
number = {8},
pages = {e70150},
doi = {10.1002/jbm.b.70150},
pmid = {42631411},
issn = {1552-4981},
support = {PUP-24-8//Pharos University in Alexandria/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced ; *Chitosan/chemistry/pharmacology ; *Quercetin/pharmacology/chemistry/pharmacokinetics ; *Lipopolysaccharides/toxicity ; *Silicon Dioxide/chemistry/pharmacology ; *Tamoxifen/pharmacology/chemistry/pharmacokinetics ; Rats ; Mice ; Male ; },
abstract = {Cholinergic dysfunction, oxidative stress, neuroinflammation, and proteinopathies are among the major hallmarks of Alzheimer's disease (AD). This study aimed to develop and evaluate the therapeutic potential of multilayered silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with quercetin (QUR) and tamoxifen (TAM) in an LPS-induced neuroinflammatory murine model exhibiting AD-like neuropathological alterations associated with bacterial endotoxin exposure. Molecular docking and target prediction analyses suggested that TAM may exert partial cholinesterase inhibitory activity and potentially interact with muscarinic receptor- and epidermal growth factor receptor (EGFR)-associated pathways, which are implicated in neuroinflammation and oxidative stress regulation. The resulting silica-based/chitosan-coated nanoparticles (Si@CsNPs) co-loaded with QUR and TAM (QUR/TAM-Si@CsNPs) were spherical in shape, exhibited a core-shell architecture, and demonstrated high loading efficiencies for QUR (93.1% ± 2.56) and TAM (84.27 ± 3.66), with a mean particle diameter of approximately 135 nm as determined by TEM. Behavioral assessment using Morris Water Maze revealed that lipopolysaccharide (LPS) administration impaired spatial learning and memory in rats; these effects were significantly ameliorated by QUR/TAM-Si@CsNPs treatment, to a greater extent than Si@CsNPs loaded individually with QUR or TAM. Biochemical, apoptotic, and histopathological analyses further demonstrated that treatment with QUR/TAM-Si@CsNPs normalized acetylcholinesterase activity, Tau protein level, β-amyloid accumulation, pro-inflammatory mediators, and apoptotic indices while preserving hippocampal architecture. Collectively, these findings demonstrate that QUR/TAM-Si@CsNPs exert combined anti-inflammatory and neuroprotective effects, highlighting their promise as a multifunctional nanotherapeutic strategy against LPS-associated neurodegenerative and AD-like neuropathological alterations.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology/chemically induced
*Chitosan/chemistry/pharmacology
*Quercetin/pharmacology/chemistry/pharmacokinetics
*Lipopolysaccharides/toxicity
*Silicon Dioxide/chemistry/pharmacology
*Tamoxifen/pharmacology/chemistry/pharmacokinetics
Rats
Mice
Male

@article {pmid42631497,
year = {2026},
author = {Gopal, RK and Pathoor, NN and Ganesh, PS},
title = {Eubiosis and dysbiosis in periodontitis-related systemic diseases.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70188},
pmid = {42631497},
issn = {1943-3670},
abstract = {BACKGROUND: This narrative review examines the eubiosis-dysbiosis spectrum in periodontitis and its systemic implications. Evidence is drawn from the literature through 2026; as a narrative review, some selection bias cannot be excluded. Periodontitis, affecting 10%-15% of adults globally, drives systemic health disorders through microbial dysbiosis.

OBJECTIVES: This narrative review examines microbial ecological shifts in periodontitis and their implications for cardiovascular disease (CVD), diabetes mellitus (T2D), neurodegenerative disorders, rheumatoid arthritis (RA), and other systemic conditions.

METHODS: We have synthesized the current evidence on oral microbiome transitions from eubiosis to dysbiosis, focusing on mechanistic pathways linking periodontal disease to systemic health outcomes.

RESULTS: Periodontal dysbiosis may influence systemic health through mechanisms including bacteremia, chronic inflammation, molecular mimicry, and microbiome axis interactions. Individuals with periodontitis show 1.5 to 2-fold increased cardiovascular risk, bidirectional relationships with diabetes (HbA1c reductions of 0.3%-0.5% following periodontal treatment), and associations with Alzheimer's disease, rheumatoid arthritis, and inflammatory bowel disease. Key pathogens including Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Fusobacterium nucleatum have been proposed as keystone species capable of remodeling microbial communities and potentially contributing to systemic effects.

CONCLUSIONS: Understanding the eubiosis-dysbiosis spectrum provides crucial insights into oral-systemic health connections and offers therapeutic targets for managing both periodontal and systemic diseases. Integrated medical-dental care approaches, precision medicine strategies, and microbiome-based therapeutics represent promising future directions.},
}

@article {pmid42631776,
year = {2026},
author = {Dineshbhai, TK and Rafaliya, D and Singh, A and Maheshwari, S and Lalan, M and Chakraborthy, GS},
title = {Emerging diagnostic biomarkers and therapeutic targets in Alzheimer's disease.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42631776},
issn = {1568-5608},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the most common cause of dementia in the world. Cognitive decline, memory problems, behavioral disturbances, and, finally, loss of functional independence characterize it. AD has risen and continues to increase globally, especially among aging people. A team of researchers at the University of Alberta says that we need faster, better diagnosis and treatment of AD. It elaborates on the progressive understanding of AD pathophysiology, biomarkers, emergent targets, and the latest delivery solution. The paper covers and discusses various disease-causing mechanisms like plaque formation, tau hyperphosphorylation, etc., which causes AD. Research is also being undertaken on the role of genetic and epigenetic factors in the pathogenesis and evolution of diseases, including but not limited to APOE polymorphisms, DNA methylation, modifications of histones, and non-coding RNAs. Researchers have discovered biomarkers relevant to AD, particularly those found in CSF and blood. The biomarkers include Aβ42, phosphorylated tau, neurofilament light chain, GFAP, and TREM2. Other biomarkers include salivary, urinary, neuroimaging, and digital. Next come the therapeutic strategies targeting amyloid aggregation, tau pathology, and other types of dysfunctions. Recent developments in monoclonal antibodies, kinase inhibitors, anti-inflammatory agents, neurotrophic agents, and antioxidant therapies are stressed. Moreover, nanotechnology-based and targeted delivery systems being developed for drugs include, but are not limited to, liposomes, polymeric nanoparticles, dendrimers, nanoemulsions, and intranasal formulations to enhance blood-brain barrier permeability. A combination of biomarker-guided diagnostics with mechanism-based therapies might enable precision medicine approaches and improve clinical outcomes in AD.},
}

@article {pmid42632150,
year = {2026},
author = {Chenxi, D and Miaomiao, W and Jiahui, F and Hongming, Z and Lu, G and Lihua, W and Ying, Z and Xiaoqing, C and Jing, Z and Yanhong, S},
title = {Technological evolution of hyperthermia: From traditional moxibustion to nanomaterial-mediated platforms for inflammatory diseases.},
journal = {Journal of thermal biology},
volume = {140},
number = {},
pages = {104557},
doi = {10.1016/j.jtherbio.2026.104557},
pmid = {42632150},
issn = {0306-4565},
abstract = {Hyperthermia, a physical therapeutic modality with unique advantages in treating inflammatory diseases, has evolved rapidly from empirical practice to precision medicine. Technologically, it has expanded from whole-body hyperthermia and traditional moxibustion to localized approaches, including photothermal, magnetothermal, ultrasound, and implantable platforms. Traditional moxibustion acts through heat and near-infrared radiation, while nanomaterials and smart devices now enable precise control over temperature, spatial targeting, and treatment duration. these modalities converge on conserved mechanisms: TRPV channel activation, HSF1-HSP70 induction, and immune modulation, which collectively alleviate inflammation and promote tissue repair in inflammatory bowel disease, osteoarthritis, and Alzheimer's disease. This review summarizes technological evolution, mechanistic insights and therapeutic applications, thereby providing a framework for developing precision hyperthermia strategies and multifunctional platforms for inflammatory diseases.},
}

@article {pmid42632510,
year = {2026},
author = {Yi, F and Ma, J and Zhao, R and Xie, Q and Lu, S and Zhang, K and Zhong, Z and OuYang, H and Qin, Y and Xu, M and Xue, Q and Wang, X and Wei, W and Liu, Y},
title = {Zonisamide improves cognitive impairment and psychiatric symptoms related with SAPAP3 in mouse models of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1033},
number = {},
pages = {179279},
doi = {10.1016/j.ejphar.2026.179279},
pmid = {42632510},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by pathological changes in Aβ&Tau, cognitive impairment, and may also manifest psychiatric symptoms. Zonisamide (ZNS) has been demonstrated its improvement of cognitive dysfunction in T2DM mice in our previous study. However, the efficacy and mechanism of ZNS in treating AD remain unclear.

AIM: We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms.

METHODS: Three-month-old 5xFAD mice were treated with ZNS (20 mg/kg, i.p.) for 12-week. The behavioral test assesses cognitive function and psychiatric symptoms. Aβ-PET/CT, immunofluorescence, and Thioflavine-S staining assessed the levels of Aβ plaques. Proteomics and Western blot analyses evaluated synapse-associated proteins, amyloid precursor protein (APP) related proteins and phosphorylated tau.

RESULTS: We discovered for the first time that ZNS significantly improved spatial learning and memory, and also alleviated psychiatric symptoms in 5xFAD. Besides, ZNS increased PSD95, SYP, BDNF, and SAP90/PSD-95-related protein 3 (SAPAP3), which plays a crucial role in compulsive-like behaviors. Importantly, siRNA-mediated knockdown of SAPAP3 in N2A/APP cells inhibited the regulatory effect of ZNS on PSD95 and NMDAR2A (NR2A). In addition, ZNS treatment reduced Aβ deposition in the brain. It also downregulated APP, p-APP (Thr668), BACE1, and PS1, and attenuated tau phosphorylation at Ser396 by inhibiting its upstream kinase ERK1/2 activity.

CONCLUSION: ZNS exerts neuroprotective effects in 5xFAD mice and improves AD-related cognitive impairment and AD-like lesions, which establishes ZNS as a promising therapeutic avenue for AD and its associated psychiatric symptoms.},
}

@article {pmid42633398,
year = {2027},
author = {Chen, H and Si, Y and Cheng, Q and Yu, Q and Cui, Z and Yu, S and Zhao, X and Jin, Y and Wang, Y and Li, M and Lu, Z},
title = {Therapeutic potential and underlying mechanisms of engineered young plasma-derived exosomes in Alzheimer's disease.},
journal = {Bioactive materials},
volume = {67},
number = {},
pages = {497-523},
pmid = {42633398},
issn = {2452-199X},
abstract = {Exosomes (EXOs) derived from the plasma of young individuals are believed to have the potential to ameliorate aging-related memory deficits. However, their specific roles and mechanisms in Alzheimer's disease (AD) therapy have not yet been systematically investigated. In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived EXOs to construct RVG-engineered EXOs (RVG-EXOs), and their therapeutic potential and underlying mechanisms in AD models were systematically evaluated. In 3×Tg AD model mice, exogenous administration of young plasma-derived EXOs and their engineered product (RVG-EXOs) revealed that RVG-EXOs could more efficiently enter brain tissue and target neurons, significantly reduce Aβ plaque and phosphorylated Tau (P-Tau) pathological deposition, restore synaptic structure, promote neuronal survival, and improve cognitive behavior. Mechanistic studies demonstrated that RVG-EXOs inhibited RPTOR expression, thereby activating the autophagy pathway and promoting the clearance of pathological proteins. Both in vitro and in vivo experiments confirmed that overexpression of RPTOR significantly suppressed the therapeutic effects of RVG-EXOs. single-cell transcriptomic profiling further revealed that RVG-EXOs not only increased neuronal proportion and modulated excitatory/inhibitory neuronal balance but also reshaped the microglial landscape by reducing deleterious disease-associated while increasing homeostatic surveillant microglia. In summary, this study not only reveals for the first time the potential value of young plasma-derived EXOs in AD treatment but also, through RVG engineering strategies and the elucidation of the RPTOR-autophagy mechanism, provides new insights for targeted therapy of neurodegenerative diseases.},
}

@article {pmid42627571,
year = {2026},
author = {Wang, Q and Wei, Y and Shen, C and Kang, W and Wang, L},
title = {CT1812 Attenuates Surgery-Induced Cognitive Impairment and Modulates TMEM97- and PGRMC1-Associated Hippocampal Stress Responses in Aged Mice.},
journal = {Neurochemical research},
volume = {51},
number = {5},
pages = {},
pmid = {42627571},
issn = {1573-6903},
support = {82201549//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Membrane Proteins/metabolism ; *Hippocampus/drug effects/metabolism ; Male ; Mice, Inbred C57BL ; Mice ; *Aging/drug effects/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy/etiology ; *Postoperative Cognitive Complications/metabolism/drug therapy ; Receptors, Progesterone ; },
abstract = {Postoperative neurocognitive disorders (PND) are common complications in older surgical patients, but druggable mechanisms linking surgical trauma to hippocampal synaptic and cognitive vulnerability remain poorly defined. The σ-2 receptor (σ-2R), encoded by transmembrane protein 97 (TMEM97), and progesterone receptor membrane component 1 (PGRMC1) intersect membrane lipid biology and synaptic stress signaling; CT1812, a pharmacological σ-2R complex modulator, has shown target engagement in early Alzheimer's disease trials, but whether this pathway participates in postoperative hippocampal injury is unknown. This study examined whether surgery-induced hippocampal stress in aged mice is associated with TMEM97 and PGRMC1 signaling and whether early CT1812 treatment can attenuate this response. Young adult (2-3 months) and aged (18-20 months) male C57BL/6J mice underwent sham operation or laparotomy; aged mice were further treated with vehicle or CT1812 (3 mg/kg, intravenous injection, days 0-3). Hippocampal molecular changes were assessed by western blotting and immunofluorescence on day 3, and behavior was evaluated by open field test (OFT) and Morris water maze (MWM) on days 6-10. Laparotomy increased hippocampal TMEM97 and PGRMC1 expression and induced anxiety-like and spatial-memory deficits preferentially in aged mice, without evidence that locomotor impairment explained the behavioral phenotype. TMEM97 and PGRMC1 were detected in neuronal nuclei (NeuN)-positive neurons, ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia, and glial fibrillary acidic protein (GFAP)-positive astrocytes in hippocampal cornu ammonis 1 (CA1), supporting multicellular pathway involvement. In aged surgical mice, CT1812 significantly reduced upregulation of TMEM97 and PGRMC1, improved OFT center-zone occupancy and MWM performance, and restored the synaptic markers postsynaptic density protein 95 (PSD95) and synaptophysin. CT1812 also normalized lipid-handling proteins, including apolipoprotein E (ApoE), ATP-binding cassette transporter A1 (ABCA1), cholesterol 24-hydroxylase (CYP46A1), and low-density lipoprotein receptor (LDLR), and reduced perilipin 2 (PLIN2) accumulation in neurons and microglia. In parallel, CT1812 attenuated a selective endoplasmic reticulum (ER) stress response involving binding immunoglobulin protein (BIP) and protein kinase R-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) signaling in hippocampal neurons, and suppressed microglial nuclear factor κB (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammatory activation, whereas C/EBP homologous protein (CHOP) was not significantly changed. These findings support a model in which postoperative injury in the aged hippocampus engages a lipid-proteostatic and inflammatory stress program associated with TMEM97 and PGRMC1, and suggest that CT1812 attenuates cognitive vulnerability by restraining this coupled response.},
}

Animals
*Membrane Proteins/metabolism
*Hippocampus/drug effects/metabolism
Male
Mice, Inbred C57BL
Mice
*Aging/drug effects/metabolism
*Cognitive Dysfunction/metabolism/drug therapy/etiology
*Postoperative Cognitive Complications/metabolism/drug therapy
Receptors, Progesterone

@article {pmid42627656,
year = {2026},
author = {Meiselbach, MK and Xu, J and Brown, T and Polsky, D},
title = {Medicare Advantage Beneficiary Enrollment Decisions Following New Complex Conditions.},
journal = {JAMA health forum},
volume = {7},
number = {8},
pages = {e262843},
pmid = {42627656},
issn = {2689-0186},
mesh = {Humans ; *Medicare Part C/statistics & numerical data ; United States ; Female ; Male ; Aged ; Chronic Disease/epidemiology ; Aged, 80 and over ; Cohort Studies ; Insurance, Medigap/statistics & numerical data ; },
abstract = {IMPORTANCE: Prior research has demonstrated higher rates of disenrollment from Medicare Advantage (MA) among people with greater health care needs. Yet, less is known about how disenrollment responds to changes in medical complexity, whether disenrollment varies by the degree of complexity, and how these patterns differ by state Medigap protections and MA plan characteristics.

OBJECTIVE: To examine changes in MA plan disenrollment following the development of new complex medical conditions and assess heterogeneity by number of conditions, state Medigap policy, and plan characteristics.

This cohort study used Medicare enrollment and claims data from 2016 to 2021. The study population included beneficiaries continuously enrolled in MA in 2016 without complex medical conditions from 2016 through 2018. A treatment group developed a new complex condition in 2019; a comparison group did not develop a complex condition through 2021. Data were analyzed from December 1, 2025, to March 1, 2026.

EXPOSURE: Development of 1 or more new complex medical conditions in 2019, including acute myocardial infarction, Alzheimer disease and related dementia, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, depression, congestive heart failure, or stroke.

MAIN OUTCOMES AND MEASURES: Annual disenrollment from the prior year MA plan, which included disenrollment to traditional Medicare (TM) or switching to another plan within MA. Difference-in-differences models with beneficiary and year fixed effects were estimated and converted to differences in percentage points.

RESULTS: The analytic sample included 1 054 926 beneficiaries, including 219 942 (mean [SD] age, 75.3 [6.3] years; 54.6% female) who developed new complex conditions in 2019 and 834 984 (mean [SD] age, 73.8 [5.6] years; 56.7% female) who did not develop a new complex condition in 2019. Developing any new complex condition was associated with an increase of 3.3 (95% CI, 3.1-3.5) percentage points (pp) in MA disenrollment, including an increase of 2.8 (95% CI, 2.7-2.9) pp in disenrollment to TM. The number of new complex conditions was associated with increased disenrollment, from 1.4 (95% CI, 1.3-1.6) pp for 1 condition to 12.8 (95% CI, 11.6-13.9) pp for 4 or more conditions. Disenrollment to TM was 1.5 (95% CI, 0.9-2.1) pp higher among beneficiaries residing in states with Medigap guaranteed issue and community rating protections.

CONCLUSIONS AND RELEVANCE: In this study, development of new complex medical conditions was associated with higher MA disenrollment, particularly to TM and in states with Medigap protections, and the magnitude increased with medical complexity. These findings highlight how changes in health status and state policy may shape Medicare coverage decisions.},
}

Humans
*Medicare Part C/statistics & numerical data
United States
Female
Male
Aged
Chronic Disease/epidemiology
Aged, 80 and over
Cohort Studies
Insurance, Medigap/statistics & numerical data

@article {pmid42622822,
year = {2026},
author = {Zhang, H and Lai, J and Wang, T and Li, T and Liu, S and Sun, DL and Chen, W and Kuang, W and Li, X and Zhang, M and Liao, Z and Xiang, X and Tuerxun, M and Zhang, X and Zhang, N and Xiao, S and Jessen, F and Yu, E and Yu, X and Wang, H},
title = {Adaptation and feasibility of the International Registry for Alzheimer's Disease and Other Dementias real-world datasets in old-age mental healthcare practice in China.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478137},
doi = {10.1177/13872877261478137},
pmid = {42622822},
issn = {1875-8908},
abstract = {BackgroundAnti-amyloid disease-modifying therapies (DMTs) for early Alzheimer's disease (AD) are entering routine care, increasing the need for harmonized, registry-ready real-world data. The International Registry for Alzheimer's Disease and Other Dementias (InRAD) proposed a minimum dataset (MDS) and extended dataset (EDS), but their applicability to psychiatry-led old age mental healthcare practices in China is uncertain.ObjectiveTo adapt the InRAD dataset for real-world AD DMT practice across multiple psychiatry institutions in China and assess the feasibility of routine data capture for the proposed MDS/EDS.MethodsWe conducted a modified Delphi consensus study and a multicenter feasibility survey. Forty-nine experts classified domains/items into the MDS or EDS using predefined agreement thresholds. Thirty-five DMT-initiating mental healthcare teams reported the routine availability of the proposed data elements.ResultsHighly consistent with InRAD, ten domains were included in the China-adapted MDS/EDS, covering patient profiles and lifestyle, diagnostic work-up and biomarkers, treatment, outcomes, safety, treatment-monitoring examinations, and registry discontinuation. However, item prioritization reflected local practice, emphasizing diagnostic traceability, functional and neuropsychiatric outcomes, caregiver burden, and structured safety capture. Feasibility results revealed that many MDS elements were collected, but the consensus-defined MDS exceeded what is currently captured in a standardized, analysis-ready format; most EDS items were moderately feasible, while WHO-5 (patient version) and DAT-scan were least feasible.ConclusionsAn InRAD-aligned dataset is broadly acceptable for psychiatry-led AD DMT practices in China, but implementation gaps remain. A phased registry approach with standardized definitions and workflow-supported capture may improve the completeness and comparability of real-world DMT evidence.},
}

@article {pmid42622974,
year = {2026},
author = {Talebi, A and Nabili, S and Alaei, M and Koohsarian, P and Doostmohammadi, A and Dadashpour, M},
title = {Exosome-derived biomarkers as non-invasive tools in stroke, Parkinson's disease, and Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42622974},
issn = {1573-7365},
mesh = {Humans ; *Exosomes/metabolism ; Biomarkers/metabolism ; *Alzheimer Disease/metabolism/diagnosis ; *Parkinson Disease/metabolism/diagnosis ; *Stroke/metabolism/diagnosis ; Animals ; MicroRNAs/metabolism ; },
abstract = {Neurological disorders, including stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), are among the most prevalent and debilitating neuropathological conditions, affecting over 50 million people globally. Effective prevention and treatment strategies require a comprehensive understanding of reliable and disease-specific biomarkers. Such insights can enhance diagnostic precision, enable early detection, and support the development of targeted therapeutic approaches. In this review, we focus on exosome-derived proteins and small non-coding RNAs as promising non-invasive biomarkers for stroke, PD, and AD, given the accessibility and stability of exosomes in biological fluids. Furthermore, we examine their potential diagnostic and therapeutic relevance, emphasizing their functional roles, specificity, and sensitivity. Finally, we discuss current limitations, emerging challenges, and future research directions to guide the advancement of exosome-based biomarker discovery and clinical translation in neurological disorders. However, we emphasize that the comparative effectiveness of exosomal microRNAs (miRNAs) versus protein biomarkers requires direct validation in future head‑to‑head cohort studies.},
}

Humans
*Exosomes/metabolism
Biomarkers/metabolism
*Alzheimer Disease/metabolism/diagnosis
*Parkinson Disease/metabolism/diagnosis
*Stroke/metabolism/diagnosis
Animals
MicroRNAs/metabolism

@article {pmid42623143,
year = {2026},
author = {Chen, Y and Ge, L and Lazarovici, P and Zheng, W},
title = {Artemisinin Attenuates Aβ1-42 Aggregation via the CaMK IV/PKA-CREB-Ace-H4 Cascade in Neuronal Cultures and 3xTg-AD Models.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-23},
doi = {10.1142/S0192415X26500667},
pmid = {42623143},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disease with a rising global prevalence, is characterized by amyloid-β (Aβ) aggregation, tau hyperphosphorylation, inflammation, oxidative damage, and neuronal apoptosis. Studies have increasingly recognized epigenetic modifications as key regulators in the development of AD. Epigenetic modifications, particularly histone acetylation, are increasingly recognized as critical regulators of cell survival and AD pathogenesis. Although artemisinin (ART) exhibits potent anti-oxidative, anti-inflammatory, and neuroprotective properties, its impact on histone acetylation in AD remains uncharacterized. This study investigated whether ART regulates histone acetylation to confer neuroprotection and rescue behavioral deficits in Alzheimer's disease models. Using SH-SY5Y cells, primary neurons, and 3xTg-AD mice, we found that ART restores histone acetylation homeostasis by enhancing histone H4 acetylation. Mechanistically, this effect is driven by the activation of the CaMK IV/PKA-CREB signaling cascade. Treatment with ART reduced ROS, improved mitochondrial function, decreased Aβ1-42 deposition, and suppressed neuronal apoptosis. However, these beneficial effects were abolished by PKA or CaMK IV inhibitors. Consequently, ART treatment significantly reduced reactive oxygen species (ROS) generation, restored mitochondrial function, decreased Aβ1-42 deposition, suppressed neuronal apoptosis, and alleviated AD-like neuropathology and cognitive deficits. Crucially, the neuroprotective and epigenetic benefits of ART were entirely abolished by pharmacological inhibitors of PKA or CaMK IV. This study is the first to demonstrate that artemisinin ameliorates AD pathology and behavioral impairments via the CaMK IV/PKA-CREB-Ace-H4 axis, establishing ART as a promising therapeutic candidate for epigenetic intervention in AD.},
}

@article {pmid42623762,
year = {2026},
author = {Wang, X and Liu, Y and Liu, J and Wang, R and Zheng, J and Deng, Z and Song, K and Zhang, D and Wang, C and Zhu, K and Zhang, J and Wu, C and Hou, G and de Vries, EFJ and Wang, Y},
title = {Translational imaging evidence for rapid reversal of amyloid and myelin pathology following deep cervical lymphatic-venous anastomosis in Alzheimer's disease.},
journal = {Nuclear medicine and biology},
volume = {160-161},
number = {},
pages = {109675},
doi = {10.1016/j.nucmedbio.2026.109675},
pmid = {42623762},
issn = {1872-9614},
abstract = {BACKGROUND: Recently, microsurgical restoration of extracranial lymphatic outflow through lymphatic-venous anastomosis (LVA) has been explored as a potential, albeit controversial, therapeutic strategy to enhance glymphatic clearance in Alzheimer's disease (AD); however, its impact on AD-related neuropathology has not yet been quantitatively or longitudinally evaluated. In this study, we performed translational PET imaging to determine whether restoring extracranial lymphatic outflow can rapidly and reversibly modulate cerebral glucose metabolism, myelin integrity, and amyloid burden in relation to cognitive improvement.

METHODS: A cervical lymphatic obstruction model was established in rats, followed by longitudinal [[18]F]FDG-PET and [[11]C]MeDAS-PET to assess cerebral glucose metabolism and myelin integrity before and after LVA, with imaging findings further validated by immunohistochemistry. A cohort of eight AD patients underwent LVA and received [[11]C]PIB and [[11]C]MeDAS PET imaging at baseline and follow-up. The imaging results were correlated with cognitive performance.

RESULTS: In Sprague-Dawley rats, cervical lymphatic obstruction led to significantly elevated cerebral glucose metabolism and reduced myelin integrity, both of which were largely restored to near-normal levels following LVA treatment, as further validated by immunohistochemical analyses. Similarly, in AD patients, LVA produced a 36.0 ± 2.1% decrease in cortical amyloid burden on [[11]C]PIB-PET (p < 0.001) and a 59.8 ± 29.0% increase in [[11]C]MeDAS uptake (p = 0.005). Subsequent correlation with MMSE scores demonstrated that short-term cognitive improvement was associated with greater myelin restoration and greater amyloid reduction.

CONCLUSION: These preliminary findings provide initial evidence that restoration of extracranial lymphatic outflow may modulate core neuropathological processes in AD, justifying further investigation in larger cohorts with appropriate control groups and randomized controlled designs to validate and extend these observations.

TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial website on April 21, 2025 (Registration No. ChiCTR2500101149).},
}

@article {pmid42624382,
year = {2026},
author = {Yenkoyan, K and Davtyan, T and Torosyan, H and Galstian, S and Chavushyan, V},
title = {Bone marrow remodeling and brain-bone marrow crosstalk in Alzheimer's disease-like neurodegeneration.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106968},
doi = {10.1016/j.bbi.2026.106968},
pmid = {42624382},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is increasingly recognized as a systemic disorder involving not only central neurodegeneration but also alterations in peripheral immune regulation and systemic homeostasis. Among these, the bone marrow represents a critical yet underexplored interface between the brain and systemic homeostasis. In the present study, we investigated whether AD-like neurodegeneration induces functional and structural remodeling of the bone marrow and whether these changes can be modulated through central neural stimulation and treatment with embryonic proteoglycans (PEG). An AD-like model was induced in adult male rats by intracerebroventricular administration of aggregated amyloid-β (Aβ1-42). Bone marrow alterations were assessed using ELISA for insulin-like growth factor-1 (IGF-1) and nerve growth factor (NGF), Western blot analysis of c-Fos and NF-κB, high-performance liquid chromatography for GABA determination, flow cytometry of hematopoietic and niche-associated cell populations, and morphological evaluation using hematoxylin and eosin and Giemsa staining. Additional modulation was performed by sequential electrostimulation of the hypothalamic supraoptic and paraventricular nuclei and by administration of embryonic proteins. Amyloid exposure significantly increased bone marrow IGF-1 levels, c-Fos expression, and NF-κB activation, accompanied by marked remodeling of marrow architecture characterized by reduced adiposity, increased hematopoietic cellularity, megakaryocytic abnormalities, and altered expression of progenitor-, neuronal-, and apoptosis-associated markers. Flow cytometry revealed shifts in specific CD3[+]CD3[+] T-cell subpopulations and increased apoptotic signaling, indicating dynamic reorganization of the hematopoietic niche. Hypothalamic stimulation and PEG treatment partially normalized these alterations, reducing inflammatory activation and restoring trophic and cellular balance. These findings demonstrate that AD-like neurodegeneration is associated with coordinated bone marrow remodeling and support the existence of a functional brain-bone marrow axis. The reversibility of these changes suggests that the bone marrow represents a biologically active and therapeutically accessible component of systemic responses to neurodegeneration, with potential relevance for future Alzheimer's disease interventions.},
}

@article {pmid42624557,
year = {2026},
author = {Halder, D and Prajapati, D and Banerjee, T and Biswas, S and Ghosh, B},
title = {Epigenetic modulators as therapeutics for neurodegenerative disorders/Alzheimer's disease.},
journal = {Methods in enzymology},
volume = {733},
number = {},
pages = {163-222},
doi = {10.1016/bs.mie.2026.06.010},
pmid = {42624557},
issn = {1557-7988},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Epigenesis, Genetic/drug effects ; Animals ; *Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; DNA Methylation/drug effects ; *Neurodegenerative Diseases/drug therapy/genetics ; Histone Deacetylases/metabolism ; },
abstract = {Epigenetic dysregulation is recognized as a primary contributor to the pathogenesis of neurodegenerative disorders, especially Alzheimer`s disease (AD). Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA regulation, govern gene expression without altering the DNA sequence, which plays a crucial role in neuronal development, synaptic plasticity, and memory formation. In AD, abnormal epigenetic alterations disrupt neuronal homeostasis, promote Aβ aggregation, tau hyperphosphorylation, and neuroinflammation, which leads to cognitive impairment. This chapter explores the assays performed and their processes using epigenetic modulators, along with their therapeutic potential in neurodegenerative diseases, especially AD. HDAC inhibitors, DNMT inhibitors, and emerging approaches, such as PROTACs for selective degradation of epigenetic enzymes, were discussed in the context of neurocognitive disorders. Preclinical and clinical evidence suggest that targeting specific HDAC isoforms (HDAC3, HDAC6, etc) can restore synaptic plasticity and improve cognitive function. This chapter further discusses recent advances, challenges in drug specificity, BBB permeability, and off-target epigenetic effects, which remain barriers to clinical translation. Case studies highlighting successful epigenetic interventions in AD models were presented to demonstrate therapeutic feasibility. Overall, epigenetic modulators present a promising therapeutic approach for neurodegeneration, and continued research integrating various assays like DNA methylation analysis, histone modification analysis, non-coding RNA analysis, neuroinflammation analysis, and functional and behavioral assays in AD models is significant in harnessing the full potential for AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/metabolism
*Epigenesis, Genetic/drug effects
Animals
*Histone Deacetylase Inhibitors/pharmacology/therapeutic use
DNA Methylation/drug effects
*Neurodegenerative Diseases/drug therapy/genetics
Histone Deacetylases/metabolism

@article {pmid42625393,
year = {2026},
author = {Okafor, NI and Abdelgader, A and Abobaker, M and Choonara, YE},
title = {A Review of the Therapeutic Potential of Stem Cell-Derived Nanocarriers to Treat Neurological Disorders.},
journal = {ChemistryOpen},
volume = {15},
number = {9},
pages = {e202500425},
pmid = {42625393},
issn = {2191-1363},
support = {//National Research Foundation (NRF) of South Africa/ ; },
mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; Animals ; *Stem Cells/cytology/metabolism ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; *Drug Carriers/chemistry ; Stem Cell Transplantation ; },
abstract = {Neurological disorders (NDs) are characterized by substantial loss of specific neurons, with Alzheimer's and Parkinson's diseases being the most frequent NDs and nearly 99% of all "foreign substances" are prohibited from entering the brain by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (CFB). These barriers, while crucial for brain protection, pose significant challenges for drug delivery, as they restrict the entry of many therapeutic agents into the brain, and this represents the primary manifestation of the absence of pathogenesis-targeting therapeutics. With significant success across multiple cell transplantation research efforts, stem cell therapy has been utilized for decades to treat neurological disorders. They work by replacing injured or lost cells directly, releasing proliferation and neurotrophic factors through autocrine and paracrine actions, suppressing neurological inflammation, and activation of endogenous brain progenitor cells. Nanocarriers derived from stem cells represent an innovative and promising therapeutic strategy for combating neurological diseases, combining faculties of regeneration of stem cells with the precision of nanotechnology. These nanocarriers possess natural biocompatibility and can efficiently cross the BBB to transport the therapeutic agents directly to affected neural tissues, thereby promoting enhanced treatment efficacy while reducing off-target effects. However, key challenges remain in large-scale production, standardization, and long-term safety. Thus, this review has examined the potential applications of stem cell extracellular vesicle (EV)-nanocarriers, mainly exosomes and recent development in the treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/therapy/drug therapy
Animals
*Stem Cells/cytology/metabolism
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
*Drug Carriers/chemistry
Stem Cell Transplantation

@article {pmid42626026,
year = {2026},
author = {Mehta, V and Singh, D and Kelman, J and Nimma, S and Lutz, H and Schnee, A and Weisman, D and Rosenbloom, MH},
title = {Real-world determinants of time to initiation of anti-amyloid treatments: comparative data from private and academic practice settings.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70436},
pmid = {42626026},
issn = {2352-8729},
abstract = {INTRODUCTION: Earlier anti-amyloid therapy (AAT) initiation results in improved clinical outcomes in Alzheimer's disease (AD). We sought to identify demographic, clinical, and disease-related factors impacting door-to-treatment times (DTTs).

METHODS: A retrospective review of AAT data was conducted at private and academic neurological practices.

RESULTS: A total of 329 patients (53.2% from private versus 46.8% academic practices), mean age 73.5 ± 7.2 (55.3% female), with most being non-Hispanic White were treated with lecanemab (81.2%) or donanemab (18.2%). DTTs were significantly reduced (p < 0.05) in both practices when diagnosis was confirmed with blood-based biomarkers (BBBs) as well as with greater clinic experience dosing AATs. DTT increased in patients with non-Medicare insurance and was not impacted by diagnosis, referral source, apolipoprotein E genotype status, or clinic distance.

DISCUSSION: Patients with private insurance may experience greater delay in DTT, whereas BBBs may reduce DTT relative to traditional confirmatory biomarkers. DTT improves with clinic experience.},
}

@article {pmid42627514,
year = {2026},
author = {Cao, Q and Shen, M and Liu, Y and Li, C and Liu, L and Zhou, J and Yue, R and Niu, D and Ren, Y and Pan, L and Yao, J and Zhang, G},
title = {The role of microglia glucose metabolism reprogramming in Alzheimer's disease treatment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261478594},
doi = {10.1177/13872877261478594},
pmid = {42627514},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment, and there remains a lack of effective treatments capable of reversing or significantly slowing disease progression. Accumulating evidence indicates that the immune function of microglia, the resident immune cells of the central nervous system, is a critical factor in regulating AD pathogenesis. Emerging research in immunometabolism further reveals that glucose metabolic reprogramming serves as a central driver of microglial phenotypic and functional differentiation. This review systematically outlines the fundamental characteristics of microglial glucose metabolism and focuses on how the dynamic metabolic reprogramming it undergoes during AD progression regulates microglial immune behavior and inflammatory responses. Building on this, we further summarize key regulatory targets within the "metabolism-immune axis" and corresponding pharmacological intervention strategies. Finally, this article discusses current challenges and future research directions in the field of microglial immunometabolism. This review aims to provide a theoretical foundation for AD intervention strategies targeting the "metabolism-immune axis" and to offer insights for the development of novel disease-modifying therapeutics.},
}

@article {pmid42619761,
year = {2026},
author = {Copeland, MH and Youngstrom, DE and Konrad, KS and Diering, GH and Letsinger, AC and Aksu, LR and Yakel, JL and Cushman, JD},
title = {Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimer's Disease Model and Wild-Type Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.07.22.739929},
pmid = {42619761},
issn = {2692-8205},
abstract = {Sleep disruption is common in Alzheimer's disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.},
}

@article {pmid42620159,
year = {2026},
author = {Wander, PL and Doherty, L and Pan, Q and Carmichael, O and Turner, R and Kuo, S and Munshi, M and Wallia, A and Noble, JM and Shah, VO and Nadkarni, NK and Mudaliar, S and Dabelea, D and Temprosa, M and Knowler, WC and Nathan, DM and Luchsinger, JA and , },
title = {Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.05.26359234},
pmid = {42620159},
abstract = {IMPORTANCE: Metformin may influence risk of dementia, with prior conflicting observations of protection or harm.

OBJECTIVE: To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS).

Prospective long-term follow-up of DPP/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline.

EXPOSURES: Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021.

MAIN OUTCOMES & MEASURES: Cognitive impairment syndromes were adjudicated in 2022- 2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes.

RESULTS: Total metformin exposure (mean ± SD) was 15.5 ±7.7 years/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 ±5.1 and 3.8 ±4.8 years/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-ε4 genotype. Randomization to metformin was also associated with significantly better memory performance over time (β=0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1).

CONCLUSIONS AND RELEVANCE: Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.

KEY POINTS: Question: Is chronic metformin treatment related to the risk of dementia and cognitive impairment?Findings: Randomization to metformin in the Diabetes Prevention Program was associated with a lower risk of dementia in the Diabetes Prevention Program Outcomes Study compared with the randomization to placebo or randomization to intensive lifestyle intervention, but the overall distribution of cognitive impairment syndromes did not differ significantly by treatment group. Randomization to metformin was also related to modestly better longitudinal performance in a memory test.Meaning: Chronic metformin treatment may decrease the risk of dementia.},
}

@article {pmid42620184,
year = {2026},
author = {Falahati, M and Ramezannejad, E and Vaez-Gharamaleki, Y and Radnia, P and Shahba, S and Rasoulian, P and Rezaei, S and Dasmeh, N and Bemanalizadeh, M},
title = {Determining the metabolic profile measured using ultra-high pressure liquid chromatography associated with Beta Amyloid burden in the brain in individuals with mild cognitive impairment.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-10065374/v1},
pmid = {42620184},
issn = {2693-5015},
abstract = {As the world's population ages, Alzheimer's disease (AD), a progressive neurodegenerative disorder, is becoming more common. The current diagnoses for AD are not precise enough to identify the disorder when it is possible to cure. An early indicator of Alzheimer's is the assessment of beta-amyloid by positron emission tomography (PET) score, a substantial decrease in the brain's metabolomics. Furthermore, Metabolomics can be detected by UPLC (ultra-high pressure liquid chromatography). This study investigates the link between metabolic profiles and beta-amyloid load in AD in order to shed light on possible biomarkers for disease progression. The data from 59 people who have been diagnosed with moderate cognitive impairment (MCI) is extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). This study uses ultra-high-performance liquid chromatography (UPLC) to investigate the correlation between baseline metabolic data and changes in amyloid PET scores. Seven metabolites, including DOPA, Methionine Sulfoxide (Met.SO), Tryptophan Betaine, choline, leucine, valine, and FA (18:2), seem to have a substantial connection with amyloid PET scores. These can be used as early indications of AD progression, especially Met.SO is particularly relevant when considering time interaction. Understanding the metabolic alterations associated with amyloid load can pave the way for future research incorporating metabolites into a therapeutic treatment that can be identified as crucial to the illness's progression.},
}

@article {pmid42620424,
year = {2026},
author = {McGill, CJ and Christensen, A and Namvari, S and Thorwald, MA and Anson, H and Vermulst, M and Finch, CE and Benayoun, BA and Pike, CJ},
title = {17α-Estradiol Confers Limited Protection Against APOE4 Phenotypes in Middle-Aged Female Mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.08.06.743074},
pmid = {42620424},
issn = {2692-8205},
abstract = {Longevity-promoting interventions represent a promising strategy to mitigate brain aging and reduce Alzheimer's disease (AD) risk. The NIA Interventions Testing Program identified the weak estrogen 17α-estradiol (17αE2) as a compound that extends healthspan and lifespan in mice, with effects observed primarily in males. Our recent work demonstrated that 17αE2 healthspan benefits were modulated by human apolipoprotein E (APOE) genotype such that aging phenotypes were improved more strongly in middle-aged male mice with targeted-replacement of the AD-associated APOE4 allele compared to APOE3 , the risk neutral and most common APOE allele. Here, we tested whether APOE -dependent, AD-relevant benefits of 17αE2 observed in males extend to females. Specifically, we treated 12-month-old APOE3 and APOE4 targeted-replacement female mice for 6 months with chow containing 0 or 14.4ppm 17αE2. We find that relative to APOE3 , APOE4 genotype largely exhibits more robust systemic phenotypes associated with aging, including increased adiposity, impaired glucose tolerance, and reduced energy expenditure. Further, we observe that treatment with 17αE2 yields modest improvements in some outcomes, including decreased adiposity and increased lean mass, glucose tolerance, and energy expenditure, though significant benefits are found only in APOE4 females. In the CNS, we observed mixed effects of APOE genotype on behavioral performance and indices of brain aging, with APOE4 females performing worse in the Barnes Maze and having higher levels of the AD-related peptide soluble β-amyloid, but no APOE genotype differences in cortical lipid raft oxidative damage. In contrast to its systemic effects, 17αE2 did not significantly improve neural outcomes in APOE3 or APOE4 females. These findings address the impact of biological sex on established protective effects of a longevity-promoting intervention against APOE4 phenotypes, which have significant relevance to the prevention of age-related conditions including metabolic dysfunction, cognitive impairment and vulnerability to AD.},
}

@article {pmid42621237,
year = {2026},
author = {Xue, WY and Li, X and Li, WT and Qin, BZ and Wang, CZ and Liu, T and Wang, M},
title = {Post-marketing safety signals and report-level ARIA-E stratification for lecanemab and donanemab: an integrated FAERS and WHO-VigiAccess pharmacovigilance study.},
journal = {Therapeutic advances in drug safety},
volume = {17},
number = {},
pages = {20420986261473013},
pmid = {42621237},
issn = {2042-0986},
abstract = {BACKGROUND: Anti-β-amyloid monoclonal antibodies provide a disease-modifying treatment approach for Alzheimer's disease, but post-marketing safety concerns remain, particularly amyloid-related imaging abnormalities (ARIA). Real-world studies have mainly described adverse event spectra and disproportionality signals, whereas report-level amyloid-related imaging abnormalities with edema or effusion (ARIA-E) risk stratification remains less well characterized.

OBJECTIVES: To compare post-marketing adverse event profiles of lecanemab (LEC) and donanemab (DON), identify report-level factors associated with ARIA-E, and develop a machine learning model for ARIA-E risk stratification.

DESIGN: Retrospective pharmacovigilance study using spontaneous reporting databases.

METHODS: Adverse event reports for lecanemab and donanemab were analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) and WHO-VigiAccess. FAERS disproportionality analyses were performed at the Preferred Term and System Organ Class levels using frequency-based and Bayesian methods. Time-to-onset and serious-outcome patterns were further explored. Multivariable logistic regression was used to examine factors associated with report-level ARIA-E. An extreme gradient boosting (XGBoost) model was developed using temporally split FAERS datasets with nested cross-validation and temporal external validation.

RESULTS: FAERS included 2961 lecanemab and 1542 donanemab primary suspect reports; WHO-VigiAccess included 2525 lecanemab- and 1450 donanemab-related reports. Across databases, adverse event profiles were dominated by neurological events, with ARIA-related events representing the central safety signals. Serious outcomes clustered mainly in the early treatment period and attenuated over time. In complete-case regression, no overall difference in ARIA-E reporting odds was observed between donanemab and lecanemab, whereas a significant donanemab-by-body weight interaction was identified. The XGBoost model showed modest discrimination, with area under the receiver operating characteristic curve values of 0.677 in internal validation and 0.630 in temporal external validation. Calibration was suboptimal, and decision curve analysis suggested limited net benefit mainly within low-threshold ranges.

CONCLUSION: ARIA-related and other neurological events remain the principal post-marketing safety concern for lecanemab and donanemab. The XGBoost model may support report-level risk prioritization, particularly during early treatment, but should not be used as a diagnostic substitute or a source of precise individualized risk estimates.},
}

@article {pmid42622140,
year = {2026},
author = {Greenberg, SM and Iadecola, C and Chou, SH and Cogswell, PM and Elkind, MSV and Hicks, WJ and Le, C and Levine, DA and Lipton, R and Massimo, L and Mohl, SM and Seshadri, S and Snyder, HM and Yaffe, K and Zachrison, KS and , },
title = {Amyloid-Related Imaging Abnormalities Summit Special Proceedings: Cardiovascular and Stroke Considerations for β-Amyloid Immunotherapy in Alzheimer Disease.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e048108},
doi = {10.1161/JAHA.125.048108},
pmid = {42622140},
issn = {2047-9980},
abstract = {BACKGROUND: New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms.

METHODS: The American Heart Association convened 75 multidisciplinary experts for the Amyloid-Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β-Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus-based guidance for clinicians.

RESULTS: This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co-occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision-making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions.

CONCLUSIONS: Building on lessons learned from the establishment of stroke systems of care, the consensus-based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground-breaking therapies.},
}

@article {pmid42622750,
year = {2026},
author = {Fu, C and Li, Q and Yang, Y and Gu, S and Zhao, W and Yao, X and Liu, H},
title = {Discovery of novel RIPK3 inhibitors by virtual screening and bioactivity evaluation.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42622750},
issn = {1573-501X},
support = {0012/2025/ASJ and 0043/2023/AFJ//the Science and Technology Development Fund of Macao SAR/ ; },
abstract = {As the most common chronic neurodegenerative disease, Alzheimer's disease (AD) has limited effective treatment options, highlighting the critical urgency of developing new therapeutic drugs. Receptor-interacting protein kinase 3 (RIPK3) is a key regulatory protein in the process of cell necroptosis and is also a potential target for AD. Existing inhibitors are not suitable for clinical treatment of AD due to problems such as insufficient activity, high toxicity, and poor selectivity. Therefore, the discovery of novel RIPK3 inhibitors is necessary and urgent. This study proposes and applies an integrated virtual screening strategy based on molecular fingerprint similarity, pharmacophore models, molecular docking, and molecular dynamics (MD) simulation. Using this workflow, we selected 54 compounds from approximately 9.7 million compounds for in vitro biological validation. In vitro kinase activity assays showed that three compounds (8019 - 0682, STK930700, and T72029) exhibited good inhibitory activity against RIPK3, with IC50 values of 1.684 µM, 3.002 µM, and 7.592 µM. Among them, 8019 - 0682 and T72029 demonstrated good cytoprotective effects in the TNF-α-induced L929 cell necroptosis model, with EC50 values of 2.135 µM and 15.891 µM. Finally, MD simulations and binding free energy calculations for the three compounds revealed a crucial hydrogen bond interaction with the M97 residue in the RIPK3 hinge region. In summary, this study proposes a combined virtual screening strategy and offers three promising lead compounds targeting RIPK3 for AD treatment.},
}

@article {pmid42611062,
year = {2026},
author = {Biswas, B and Gabb, VG and Blackman, J and Morrison, H and Coulthard, E and Roudaut, A},
title = {"Like Taking Part in Star Wars": Qualitative Study Using Thematic Analysis to Explore the Acceptability and Experiences of Older Adults Participating in Remote Longitudinal Sleep and Dementia Research.},
journal = {Journal of medical Internet research},
volume = {28},
number = {},
pages = {e88094},
pmid = {42611062},
issn = {1438-8871},
mesh = {Humans ; Aged ; Female ; Male ; *Dementia/physiopathology ; *Sleep ; Cognitive Dysfunction/physiopathology ; Aged, 80 and over ; Longitudinal Studies ; Qualitative Research ; Remote Patient Monitoring ; Digital Health ; },
abstract = {BACKGROUND: Sleep disturbance is a common symptom of and potential risk factor for neurodegeneration and dementia. Remote monitoring technologies and increasing digital literacy offer promise for monitoring symptoms and treatment responses via sleep and cognitive assessments from patients' homes. However, the acceptability of remote sleep and circadian research in older adults with and without cognitive impairment is not known.

OBJECTIVE: This study aimed to explore and describe the barriers, facilitators, and user experience of older adults participating in longitudinal sleep and dementia research using remote monitoring technologies.

METHODS: Older adults with mild cognitive impairment (MCI) or dementia due to probable Alzheimer disease or Lewy body disease and age-matched controls participated in an 8-week remote study involving multimodal assessments of sleep and cognition, including actigraphy, wireless electroencephalography, web-based cognitive tasks, and serial saliva samples. Participants were asked for feedback via questionnaires during the study at 2 time points and purposively invited to complete end-of-study interviews about their experiences. The Capability, Opportunity, Motivation-Behavior model of behavior change, and the extended Unified Theory of Acceptance and Use of Technology, were used to guide questionnaire and interview topic guide development. Inductive reflexive thematic analysis was undertaken, with components from the models used as sensitizing concepts.

RESULTS: A total of 14 participants (9 with MCI or dementia, 5 controls) completed end-of-study interviews, and 28 participants (9 with MCI or dementia, 19 controls) completed questionnaires. Six key themes were identified: (1) "Perceived value as motivation," (2) "Trust and simplicity as cornerstones in user experience," (3) "Adjusting to study participation over time," (4) "Adherence, accuracy, and getting it right," (5) "Social support as a facilitator and a barrier," and (6) "Reflections, realities, and uncertainties around sleep."

CONCLUSIONS: Older adults with and without cognitive impairment were motivated to engage in longitudinal remote sleep research and provide good quality data. Acceptability was related to burden, usability, and reliability of devices, having sufficient support, and ability to build study tasks into a routine. In repeated cognitive tasks, varying task content and difficulty, and allowing flexibility in timing may avoid fatigue and frustration. Future studies should aim to identify effective strategies for recruiting diverse populations, particularly those with limited technology experience or from underserved communities, to ensure equitable participation and representation in research. Providing education on the importance of sleep for brain health and technology use may be beneficial.},
}

Humans
Aged
Female
Male
*Dementia/physiopathology
*Sleep
Cognitive Dysfunction/physiopathology
Aged, 80 and over
Longitudinal Studies
Qualitative Research
Remote Patient Monitoring
Digital Health

@article {pmid42611282,
year = {2026},
author = {Ahmad, S and Mei, J and Wang, C and Jia, M and Nouman, MF and Ai, H},
title = {Modulation Mechanisms of Transmembrane Domain Flexibility in Amyloid Precursor Protein and Notch: A Coarse-Grained Simulation Study on the Impact of Upper and Lower Leaflet Composition in Liquid-Ordered and Liquid-Disordered Ternary Bilayer Membranes.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {42},
number = {32},
pages = {23197-23215},
doi = {10.1021/acs.langmuir.6c00533},
pmid = {42611282},
issn = {1520-5827},
support = {ZR2022MB073//Shandong Provincial Natural Science Foundation of China/ ; },
mesh = {*Lipid Bilayers/chemistry/metabolism ; *Receptors, Notch/chemistry/metabolism ; *Amyloid beta-Protein Precursor/chemistry/metabolism ; *Molecular Dynamics Simulation ; Protein Domains ; Cholesterol/chemistry ; Phosphatidylcholines/chemistry ; },
abstract = {Alzheimer's disease (AD) and Notch-related pathologies are linked to dysregulated γ-secretase cleavage of amyloid precursor protein (APP) and Notch transmembrane domains (TMDs). However, γ-secretase inhibitors for AD often disrupt Notch signaling, necessitating strategies to selectively modulate substrate cleavage. This study employs coarse-grained molecular dynamics simulations to investigate how lipid bilayer composition─specifically liquid-ordered (Lo) and liquid-disordered (Ld) phases with varying cholesterol (Chol), palmitoyl-sphingomyelin, and 1,2-dioleoyl-sn-phosphatidylcholine ratios─impacts the flexibility and stability of APP and Notch TMDs. Our key findings reveal that Chol-rich Lo phases enhance APP TMD flexibility, promoting γ-secretase cleavage and Aβ production, while Notch TMD stability is largely unaffected by Chol, favoring Ld phases, replicating perfectly the existing experimental observations and resolving several conflicting perspectives. A critical innovation lies in identifying asymmetric lipid compositions (e.g., Chol-enriched lower leaflets) as regulators of APP-Notch selectivity. These results highlight membrane microenvironment engineering as a promising therapeutic avenue to decouple APP and Notch processing. Future work should validate these findings experimentally and explore lipid-based modulators for AD treatment with reduced side effects.},
}

*Lipid Bilayers/chemistry/metabolism
*Receptors, Notch/chemistry/metabolism
*Amyloid beta-Protein Precursor/chemistry/metabolism
*Molecular Dynamics Simulation
Protein Domains
Cholesterol/chemistry
Phosphatidylcholines/chemistry

@article {pmid42611390,
year = {2026},
author = {Oria, RS and Akpang, KE and Ben, RB and Aneke, VO and Ushie, IE and Uchenna, MJ and Ikong, GB and Uket, JI and Woko, C and Ijomone, OM},
title = {Hesperidin attenuates aluminum chloride-induced cognitive impairment by modulating ERK/MAPK Signaling, tau protein immunoexpression, neuroinflammation, and microglial activation in mice.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42611390},
issn = {1573-7365},
mesh = {Animals ; *Hesperidin/pharmacology/therapeutic use ; Aluminum Chloride ; *Microglia/drug effects/metabolism ; Male ; *tau Proteins/metabolism/biosynthesis ; Mice ; *MAP Kinase Signaling System/drug effects ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Maze Learning/drug effects ; Aluminum Compounds ; },
abstract = {Aluminum chloride (AlCl3) is widely used to model Alzheimer's-related neurotoxicity and cognitive decline. Hesperidin, a citrus flavanone with antioxidant and anti-inflammatory properties, has unclear neuroprotective mechanisms against aluminum-induced neurodegeneration. This study investigated hesperidin's neuroprotective effects against AlCl3-induced cognitive impairment in mice, focusing on ERK/MAPK signaling, tau expression, neuroinflammation, and microglial activation. Mice received AlCl3 (100 mg/kg) daily for four weeks, hesperidin (100 mg/kg), both, or vehicle, with hesperidin administered during weeks 3 and 4 in the co-treated group. Cognitive function was assessed using the Morris water maze and Y-maze tests. TNF-α and IL-1β were quantified in brain tissue. IBA1-positive microglial density, ERK immunoreactivity, and tau expression were evaluated immunohistochemically in the hippocampal CA3 region and the prefrontal cortex. AlCl3 impaired spatial and working memory, elevated pro-inflammatory cytokines, increased microglial activation, and upregulated ERK and tau immunoexpression in both regions. Hesperidin co-treatment significantly rescued cognitive deficits, attenuated neuroinflammation, reduced microglial reactivity, modulated ERK signaling, and decreased tau overexpression. These findings demonstrate that hesperidin protects against AlCl3-induced neurodegeneration by concurrently modulating neuroinflammatory and kinase-dependent pathways, supporting its therapeutic potential in aluminum-related tauopathies.},
}

Animals
*Hesperidin/pharmacology/therapeutic use
Aluminum Chloride
*Microglia/drug effects/metabolism
Male
*tau Proteins/metabolism/biosynthesis
Mice
*MAP Kinase Signaling System/drug effects
*Cognitive Dysfunction/chemically induced/metabolism/drug therapy
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced
*Neuroprotective Agents/pharmacology/therapeutic use
Maze Learning/drug effects
Aluminum Compounds

@article {pmid42612268,
year = {2026},
author = {Li, Z and Sun, T and Han, M and Xiao, B and Liu, S and Zhang, J and Ma, J and Ma, H and Yang, J and Zhang, Z},
title = {Deep learning-driven discovery and optimization of natural LSD1 inhibitors for the treatment of Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110396},
doi = {10.1016/j.bioorg.2026.110396},
pmid = {42612268},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with limited effective disease-modifying treatments. Lysine-specific demethylase 1 (LSD1) has emerged as a promising target for AD therapy. However, current LSD1 inhibitors for AD still suffer from poor brain permeability, off-target toxicity, and chemical-scaffold scarcity. Herein, we developed a multimodal deep learning model (PLM-CAFT-DTA) for drug-target affinity (DTA) prediction. This model integrates ChemBERTa, ESM-2, graph attention, and cross-attention fusion to achieve high prediction precision. Using this model combined with virtual screening and molecular simulation, we identified silybin as a hit compound from a library of over 70,000 natural products. After rational modification, compound S3 was obtained with significantly improved LSD1 inhibition (IC50 = 2.30 μM), approximately 7-fold more potent than the silybin. In vitro assays showed that S3 exhibited favorable neuroprotective and antioxidant activities. In APP/PS1 mice, S3 upregulated hippocampal H3K9me2, suppressed neuroinflammation and Aβ deposition, and improved cognitive function. By addressing unmet demands for AI-assisted anti-AD lead discovery, this study provides a generalized DTA tool for early-stage drug development, and identifies S3 as a novel LSD1 inhibitor with potent anti-AD efficacy.},
}

@article {pmid42612783,
year = {2026},
author = {Yu, Z and Wang, Y and Yang, Y},
title = {Autophagy as a mechanistic link between physical exercise and Alzheimer's disease.},
journal = {Neuroscience},
volume = {614},
number = {},
pages = {307-317},
doi = {10.1016/j.neuroscience.2026.08.026},
pmid = {42612783},
issn = {1873-7544},
abstract = {Alzheimer's Disease (AD), the most prevalent cause of dementia worldwide, is a neurodegenerative disorder that currently has no cure. A growing body of evidence suggests that physical exercise is a potential non-pharmacological strategy in the treatment of AD. Recent findings highlight the involvement of autophagy in the modulatory actions of physical exercise for AD. Here, we present a narrative review of the current knowledge on how exercise impacts AD, specifically focusing on its regulation of autophagic activity in animal models of AD. Evidence from rodent studies further demonstrates that exercise may influence AD-related pathology through autophagy-lysosomal regulation, lysosomal homeostasis, and mitochondrial quality control, but direct human evidence remains limited. This review uniquely positions exercise-induced autophagy regulation as a central mechanistic hub, offering a novel paradigm for developing lifestyle-based interventions for AD.},
}

@article {pmid42613144,
year = {2026},
author = {Valverde, A and Blasco, H and Corcia, P and Herault, O and Magistretti, P and Herault, L and Cali, C and Bartesaghi, L and Stone, J and Mitrofanis, J},
title = {Exploring the effect of red and near-infrared light on neurodegenerative disease: A focus on amyotrophic lateral sclerosis, Charcot's devastating disease of the motor system.},
journal = {International review of neurobiology},
volume = {189},
number = {},
pages = {205-236},
doi = {10.1016/bs.irn.2026.01.013},
pmid = {42613144},
issn = {2162-5514},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/therapy/radiotherapy ; Animals ; *Infrared Rays/therapeutic use ; Red Light ; *Neurodegenerative Diseases/therapy ; },
abstract = {All neurodegenerative diseases, from Alzheimer's disease to amyotrophic lateral sclerosis (ALS), are characterised by a relentless and progressive degeneration of neurones. The degenerating neurones suffer from mitochondrial dysfunction, glutamate excitotoxicity, metabolic disorder and atypical protein aggregations; there is also widespread neuroinflammation and damage to the neurovascular unit across the nervous system. Unfortunately, there is no current treatment option that addresses all, if not many, of these striking abnormalities, one that stops or even slows the progression of the disease (ie neuroprotective). In this chapter, we explore the potential effectiveness of red and near infrared light (R-NIr) on ALS, one of the most devastating of all the neurodegenerative diseases. This condition impacts the motor system, from the cerebral cortex and brainstem to the spinal cord, as well as many skeletal muscles. Individuals suffer greatly and the survival period after onset of the first signs is often very short, averaging just over 2 years, as against 4-8 years in dementia. We outline two main reasons why R-NIr may have positive outcomes in ALS; (1) R-NIr has been shown to be neuroprotective in many other neurodegenerative diseases, improving cell function and survival, and; (2) unlike many other treatments attempted previously, R-NIr addresses many, if not all features of pathology associated with ALS. In summary, we suggest that R-NIr, with its multi-modal effect, could be a valuable treatment option for patients with ALS, particularly if the treatment is started early, before the development of excessive cellular damage.},
}

Humans
*Amyotrophic Lateral Sclerosis/therapy/radiotherapy
Animals
*Infrared Rays/therapeutic use
Red Light
*Neurodegenerative Diseases/therapy

@article {pmid42613627,
year = {2026},
author = {Jamali, MC and Shafie, A and Alqahtani, AJ and Al-Samawi, RI and Alyami, HM and Ashour, AA and Felemban, MF and Mansuri, N and Tayeb, FJ and Ahmad, I and Mudhafar, M and Sheweita, SA},
title = {Advances in the clinical application of mesenchymal stem cells for neurological disorders.},
journal = {Stem cell research & therapy},
volume = {17},
number = {1},
pages = {},
pmid = {42613627},
issn = {1757-6512},
mesh = {Humans ; *Mesenchymal Stem Cell Transplantation/methods ; *Mesenchymal Stem Cells/cytology/metabolism ; *Nervous System Diseases/therapy/pathology ; Animals ; Amyotrophic Lateral Sclerosis/therapy/pathology ; Alzheimer Disease/therapy/pathology ; },
abstract = {Therapeutic approaches employing mesenchymal stem cells (MSCs) have emerged as a promising avenue for investigating treatments for neurological disorders. This strategy aims to capitalize on the biological properties of MSCs to support the repair of damaged neural tissue and modulate pathological processes. This review provides a comprehensive overview of the current clinical evidence regarding MSC applications in major neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and other pertinent disorders. Across clinical studies, MSC administration has generally demonstrated a favorable safety profile and procedural feasibility. However, therapeutic efficacy remains variable and inconsistent across trials. Importantly, differences in MSC sources, manufacturing procedures, delivery routes, dosing strategies, and patient selection contribute substantially to the heterogeneity of reported outcomes. Therefore, the current body of evidence supports the safety of MSC-based interventions, but their clinical effectiveness has not yet been consistently demonstrated. Future progress will depend largely on the standardization of cell preparation and treatment protocols, improved biomarker-driven patient stratification, and rigorously designed large-scale randomized trials.},
}

Humans
*Mesenchymal Stem Cell Transplantation/methods
*Mesenchymal Stem Cells/cytology/metabolism
*Nervous System Diseases/therapy/pathology
Animals
Amyotrophic Lateral Sclerosis/therapy/pathology
Alzheimer Disease/therapy/pathology

@article {pmid42613696,
year = {2026},
author = {Abubakar, MD and Dahiya, R and Nama, L and Goyal, K and Ambawatiya, A and Bishnoi, M and Rai, A and Murti, K and Kumar, N},
title = {An Innovative Strategy for Treating Neurodegenerative Disorders through Exosome-based Smart Delivery Systems: A Comprehensive Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273453626260724060812},
pmid = {42613696},
issn = {1996-3181},
abstract = {Alzheimer's and Parkinson's diseases are devastating brain disorders. The complex pathophysiology of the diseases and the lack of effective treatments have left them almost unexplored and untreatable. One potential approach to PD and AD therapy development is through exosomes, a delivery system that can be translated from innovative delivery techniques into clinical use. These exosome-based therapeutics will require thorough testing, research-driven refinement of engineering methods, and collaboration among scientists, clinicians, and industry to develop exosome therapeutics for clinical use. This review explores the biological properties of exosomes, recent engineering advances to improve their therapeutic potential, and new methods to leverage their versatility for selective delivery of remedial agents to the brain. In addition, preclinical evidence demonstrates that exosomes can modulate amyloid-β aggregation, α-synuclein pathology, neuroinflammation, and mitochondrial dysfunction. Yet difficulties related to mass production, maintaining quality, and obtaining regulatory approvals to bring them into clinical practice remain significant limiting factors. The authors point out the therapeutic advantages and drawbacks of exosome-based drug delivery systems. Besides, it provides a roadmap for harnessing these methods effectively as medical interventions for Alzheimer's and Parkinson's disorders, thereby promoting more studies in the area. Finally, we outline a conceptual model for translating novel exosome-based delivery methods into clinically applicable treatment modalities for Alzheimer's and Parkinson's diseases, thereby encouraging continued exploration in this promising field of research.},
}

@article {pmid42613698,
year = {2026},
author = {Sharma, A and Singh, P},
title = {Synergistic Role of Caffeic Acid with Conventional Neuroprotective Drugs: Potential of Combination Therapy for Managing Alzheimer's Disease.},
journal = {Recent advances in inflammation & allergy drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0127722708476112260728060133},
pmid = {42613698},
issn = {2772-2716},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a complex neurodegenerative disease involving amyloid-β accumulation, formation of neurofibrillary tangles, oxidative stress, and inflammation. Current treatment options include symptomatic agents such as Acetylcholinesterase Inhibitors (AChEIs) and memantine. The present review discusses the therapeutic potential of Caffeic Acid (CA) as an adjunctive agent to conventional anti-Alzheimer's treatments, focusing particularly on its pharmacodynamics and pharmacokinetics.

METHODS: An extensive search of the literature was carried out from the years 2000 to 2025 using databases such as PubMed, Scopus, Web of Science, Science Direct, Embase, Medline, Google Scholar, and others. All in vitro, in vivo, and in silico studies that have evaluated CA alone or in combination with AChEIs and memantine were included.

RESULTS: The existing literature suggests that CA has antioxidant, anti-inflammatory, and weak cholinesterase inhibition properties, while AChEIs and memantine mainly target neurotransmission. The results suggest that CA, when combined with other anti-Alzheimer's agents, provides superior neuroprotective properties compared to monotherapy in various animal models. Nevertheless, current data support more additive rather than synergistic actions of CA with AD medications.

DISCUSSION: Pharmacokinetic issues associated with CA use are possible due to the drug's ability to interfere with cytochrome P450 and P-glycoprotein. Moreover, issues with CA pharmacokinetics, nanoparticle delivery systems, and patient compliance might affect the translation of these findings into clinical practice.

CONCLUSION: CA might be used as an auxiliary substance for treating AD. Further research on pharmacokinetic/pharmacodynamic interactions and synergy between these compounds is required.},
}

@article {pmid42613699,
year = {2026},
author = {Kulan, H},
title = {Proteomic Basis of Polypharmacological Cognitive Recovery in Down Syndrome and Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050471158260716112026},
pmid = {42613699},
issn = {1875-5828},
abstract = {INTRODUCTION/OBJECTIVE: Down Syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 and represents the most common genetic cause of intellectual disability. It is also associated with an increased risk of developing Alzheimer's Disease (AD). Although various pharmacological treatments have been shown to improve learning and memory in DS models, the underlying mechanisms of cognitive improvement remain poorly understood. This study aims to identify molecular signatures associated with pharmacological cognitive rescue across different brain regions using a machine learning-guided targeted proteomics approach.

METHODS: Gradient Boosting Tree (GBT)-based feature selection combined with Principal Component Analysis (PCA) was applied to identify reproducible proteomic signatures in cortical samples from memantine-treated mice and in hippocampal samples from RO4938581-treated mice.

RESULTS: GBT models achieved classification accuracies exceeding 80% across experimental groups, and PCA showed distinct group separation, with PC1 and PC2 accounting for more than 60% of the total variance. The consistently identified proteins across datasets include APP, RCAN1, S6/pS6, IL1B, BAX, TAU, AMPKA, BRAF, ERK, and ADARB1.

DISCUSSION: The identified proteins converge on interconnected networks linking synaptic signaling, metabolic regulation, and neuroinflammation, reflecting pathways involved in Excitation/İnhibition (E/I) imbalance and neurodegeneration. Their consistency across datasets implies that coordinated regulation of these networks, rather than isolated pathway effects, is associated with cognitive improvement. Specifically, the MAPK-ERK and AMPK-mTOR signaling pathways emerge as key integrative nodes connecting synaptic function, energy balance, and cellular stress responses. These results point to possible mechanistic overlap with Alzheimer's disease-related pathology and support a network-based, multi-target model of cognitive improvement in DS.

CONCLUSION: These results demonstrate that different pharmacological treatments converge on shared protein signatures associated with cognitive improvement in DS. This convergence supports a network- based, multi-target therapeutic approach, in which modulation of key regulatory nodes rather than single targets may underlie effective treatment strategies.},
}

@article {pmid42614235,
year = {2026},
author = {Meng, Z and Wu, H and Miao, Y and Qi, W and Sha, M},
title = {Association between different sodium-glucose co-transporter 2 inhibitors and the risk of dementia: a network meta-analysis.},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1777151},
pmid = {42614235},
issn = {1664-2392},
mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; *Dementia/prevention & control/epidemiology ; *Diabetes Mellitus, Type 2/drug therapy ; Benzhydryl Compounds/therapeutic use ; *Hypoglycemic Agents/therapeutic use ; Canagliflozin/therapeutic use ; Glucosides/therapeutic use ; },
abstract = {BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i), as key therapeutic agents for type 2 diabetes, have in recent years been recognized as potentially exerting neuroprotective effects on the central nervous system. However, systematic comparative evidence remains lacking regarding whether different SGLT2i exhibit differential effects on dementia risk. By conducting a network meta-analysis to compare the association between different SGLT2i and the risk of dementia onset, the relative efficacy of each drug in reducing dementia risk is determined.

METHODS: A systematic search was conducted across databases including PubMed, Embase, Web of Science, and the Cochrane Library, from their inception to the search cutoff date of 1 December 2025. Randomized controlled trials and observational studies comparing SGLT2i with other antidiabetic medications or placebo, and reporting dementia outcomes, were included. A network meta-analysis employing a random-effects model was conducted. Pooled effect sizes were expressed as hazard ratios with 95% confidence intervals. Relative efficacy among different drugs was ranked using the probability of ranking, whilst heterogeneity and consistency were assessed.

RESULTS: Six cohort studies involving 845,433 patients were included in this analysis. The results of the network meta-analysis indicated that canagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), Dapagliflozin (HR = 0.75, 95% CrI: 0.59, 0.98), and Empagliflozin (HR = 0.69, 95% CrI: 0.55, 0.85) significantly reduced the risk of dementia onset. Empagliflozin had the highest probability of being ranked as the most effective treatment (81.2%). However, no statistically significant differences were observed between empagliflozin and dapagliflozin or canagliflozin in the network comparisons. For Alzheimer's disease, Dapagliflozin (HR = 0.68, 95% CrI: 0.48, 0.96) and Empagliflozin (HR = 0.62, 95% CrI: 0.45, 0.87) also demonstrated significant risk reduction, whilst direct comparisons between Empagliflozin and other agents showed no significant differences. For vascular dementia, Empagliflozin (HR = 0.63, 95% CrI: 0.46, 0.87) and Canagliflozin (HR = 0.71, 95% CrI: 0.48, 0.98) also demonstrated favorable outcomes.

CONCLUSIONS: The findings of this study indicate that dapagliflozin, empagliflozin, and canagliflozin, particularly empagliflozin, demonstrate significant potential in reducing the incidence of dementia and related cognitive impairments. Compared with DPP-4 inhibitors, these agents effectively lower the risk of dementia, Alzheimer's disease, and vascular dementia, offering an effective therapeutic option for diabetic patients, particularly the elderly.},
}

Humans
*Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
*Dementia/prevention & control/epidemiology
*Diabetes Mellitus, Type 2/drug therapy
Benzhydryl Compounds/therapeutic use
*Hypoglycemic Agents/therapeutic use
Canagliflozin/therapeutic use
Glucosides/therapeutic use

@article {pmid42615643,
year = {2026},
author = {Singh, SK and Dinodiya, H and Parihar, S and Korupalli, C and Vankayala, R},
title = {Engineering ApoE3-Targeted NIR-Responsive Liposomes for Multimodal Inhibition of Amyloid-β Aggregation and Acetylcholinesterase Activity.},
journal = {ACS chemical neuroscience},
volume = {17},
number = {16},
pages = {3094-3108},
doi = {10.1021/acschemneuro.6c00315},
pmid = {42615643},
issn = {1948-7193},
support = {BT/RLF/Re-entry/17/2018//Department of Biotechnology, Ministry of Science and Technology, India/ ; 191620102067//University Grants Commission/ ; CRG/2023/001189//Department of Science and Technology, Ministry of Science and Technology, India/ ; I/SEED/RRV/20200076//Department of Science and Technology, Ministry of Science and Technology, India/ ; },
mesh = {*Liposomes ; *Amyloid beta-Peptides/metabolism ; Humans ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; Donepezil/pharmacology/administration & dosage ; *Acetylcholinesterase/metabolism ; *Apolipoprotein E3/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism/drug effects ; Indocyanine Green ; Animals ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive decline, largely driven by amyloid-β (Aβ) aggregation and dysregulated acetylcholinesterase (AChE) activity. While current pharmacological interventions utilize AChE inhibitors and Aβ antagonists, their efficacy is frequently hampered by monotherapeutic limitations, poor blood-brain barrier (BBB) permeability, and a lack of controlled release mechanisms. Herein, we report the engineering of the liposomal formulation coloaded with Donepezil (DNP) and the photothermal agent indocyanine green (ICG), followed by conjugation of ApoE3 protein (LIDA) designed for multimodal AD therapy. Surface-conjugated ApoE3 serves a bifunctional role by facilitating BBB penetration and actively inhibiting Aβ oligomerization. Upon 808 nm laser irradiation, ICG-mediated photothermal induction triggers the spatiotemporal release of DNP, significantly enhancing AChE inhibition. Furthermore, LIDA treatment effectively mitigates Aβ-induced cytotoxicity and mitochondrial dysfunction in SH-SY5Y cells. By integrating targeted delivery with NIR responsiveness, this study presents a novel, multivalent strategy to combat the complex pathological landscape of AD.},
}

*Liposomes
*Amyloid beta-Peptides/metabolism
Humans
*Cholinesterase Inhibitors/pharmacology/administration & dosage
Donepezil/pharmacology/administration & dosage
*Acetylcholinesterase/metabolism
*Apolipoprotein E3/metabolism
Alzheimer Disease/metabolism/drug therapy
Cell Line, Tumor
Blood-Brain Barrier/metabolism/drug effects
Indocyanine Green
Animals

@article {pmid42615950,
year = {2026},
author = {Hu, CJ and Huang, YH and Cho, S and Wang, BCM and Shen, SP and Newson, RS and Tang, CH},
title = {Epidemiology, Patient Characteristics, Treatment Patterns, and Costs of Mild Cognitive Impairment and Alzheimer's Disease in Taiwan.},
journal = {Value in health regional issues},
volume = {},
number = {},
pages = {101687},
doi = {10.1016/j.vhri.2026.101687},
pmid = {42615950},
issn = {2212-1102},
abstract = {OBJECTIVES: Alzheimer's disease (AD) with mild cognitive impairment (MCI) and AD are stages along the cognitive decline continuum and represent growing public health concerns. This study aimed to assess the diagnosed prevalence, claims-identified incidence, treatment patterns, healthcare costs, comorbidities, and observed mortality outcomes of individuals with AD with MCI, and AD with dementia in Taiwan claims data over a 10-year period.

METHODS: We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Individuals diagnosed with AD with MCI, or AD, between 2013 and 2022 were identified via ICD-9-CM and ICD-10-CM codes. Cross-sectional and longitudinal analyses examined epidemiology, treatment trends, costs, comorbidities, and mortality using descriptive statistics, survival analysis, and cost evaluations.

RESULTS: The estimated prevalence of AD with MCI, and AD from the claims database, increased from 109 379 cases in 2018 to 131 053 in 2022. Among pharmaceutical interventions, donepezil usage was predominant and increased over time, whereas nonpharmacologic therapies remained minimal. Healthcare costs rose with disease severity, with nonpharmacological inpatient care being the highest expense. Cardiovascular and metabolic comorbidities were prevalent and increased with severity. Observed cumulative mortality proportions increased with advancing disease severity; patients with AD with severe dementia had the highest mortality burden (41.98% at year 3).

CONCLUSION: AD with MCI and AD with dementia prevalence estimation is rising, demonstrating increasing costs and high comorbidity burdens. Disease severity is linked to higher mortality, reinforcing the need for integrated care and early cost-effective interventions to optimize outcomes in AD with MCI and AD with patients with dementia.},
}

@article {pmid42618557,
year = {2026},
author = {Jonsdotter, A and Leverin, AL and Svedin, P and Lindström, M and Ebefors, K and Carlsson, Y and Hagberg, H and Rocha-Ferreira, E},
title = {Exendin-4 improves neurodevelopmental outcome after neonatal germinal matrix hemorrhage.},
journal = {Cell death & disease},
volume = {17},
number = {1},
pages = {},
pmid = {42618557},
issn = {2041-4889},
support = {2023-02035//Vetenskapsrådet (Swedish Research Council)/ ; 2021-0056//Hjärnfonden (Swedish Brain Foundation)/ ; },
mesh = {Animals ; *Exenatide/pharmacology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Animals, Newborn ; Neurodevelopment/drug effects ; Caspase 3/metabolism ; *Peptides/pharmacology/therapeutic use ; Matrix Metalloproteinase 9/metabolism ; Rats, Sprague-Dawley ; *Venoms/pharmacology/therapeutic use ; Disease Models, Animal ; Microglia/drug effects/metabolism/pathology ; Tumor Suppressor Protein p53/metabolism ; Female ; },
abstract = {Germinal matrix hemorrhage (GMH) is a common complication in premature infants and is associated with a high risk of neurodevelopmental impairment and mortality. Currently, there are no specific neuroprotective treatments available. Exendin-4 is a drug used for the treatment of type 2 diabetes mellitus, and it has shown neuroprotective effects in several neurological disorders including Alzheimer's and Parkinson's disease. In this study, we used the preterm postnatal day 5 rat model of GMH to evaluate whether exendin-4 exerts neuroprotective effects in this setting. Our results show that in the acute phase, exendin-4 reduced microglial activation, caspase-3 activation, p53 expression, AIF-associated cell death, MMP-9 expression, and neutrophil infiltration into the hemorrhage site. Exendin-4 treatment improved neurodevelopmental outcomes in both negative geotaxis and eye-opening latency when compared to saline-treated GMH controls, and conferred gray and white matter protection as early as 48 h after injury, with persistent neuroprotection observed at 5, 11, and 35 days after GMH. Exendin-4-treated animals also showed significant recovery of motor function in the rotarod test. In summary, this study demonstrates that exendin-4 reduces brain injury in a rat model of GMH in both the short and long term and is associated with improved neurological outcome.},
}

Animals
*Exenatide/pharmacology
*Neuroprotective Agents/pharmacology/therapeutic use
Rats
Animals, Newborn
Neurodevelopment/drug effects
Caspase 3/metabolism
*Peptides/pharmacology/therapeutic use
Matrix Metalloproteinase 9/metabolism
Rats, Sprague-Dawley
*Venoms/pharmacology/therapeutic use
Disease Models, Animal
Microglia/drug effects/metabolism/pathology
Tumor Suppressor Protein p53/metabolism
Female

@article {pmid42619056,
year = {2026},
author = {Oishi, K and Adams, R and Nowrangi, MA and Zandi, PP and Lyketsos, CG},
title = {Utilizing routinely acquired clinical neuroimaging and electronic health record data to advance precision medicine in dementia care.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09540261.2026.2714142},
pmid = {42619056},
issn = {1369-1627},
abstract = {Alzheimer's disease (AD) exhibits significant clinical variability in symptom onset, progression rates, neuropsychiatric symptoms and treatment responses. This variability reflects a range of underlying biological, genetic and environmental factors. This review summarizes recent advances in leveraging real-world electronic health records (EHRs) and clinical brain MRI to enhance precision medicine in dementia care. Traditional MRI research has identified consistent subtypes of atrophy associated with AD. However, these models often struggle to apply to routine clinical imaging, which can vary widely in contrast, resolution and acquisition protocols. Recent technological developments now allow for reliable measurement of gray matter, white matter, brainstem and cerebellar structures from routine clinical scans, effectively overcoming long-standing limitations of conventional neuroimaging methods. Additionally, efforts in EHR analysis, including the use of natural language processing on unstructured clinical notes, have enabled large-scale extraction of cognitive scores, neuropsychiatric symptoms and treatment responses. By integrating structured EHR data with detailed imaging markers, researchers have enabled predictive modeling of cognitive decline and treatment responses, though generalizability across settings remains a challenge. Federated learning frameworks offer a privacy-preserving approach to collaboratively develop models across multiple institutions. Together, these strategies outline a practical, data-driven approach to individualized diagnosis, prognosis and treatment planning for dementia.},
}

@article {pmid42608702,
year = {2026},
author = {Swane, V and Biering-Sørensen, B},
title = {Posterior cortical atrophy with initial psychiatric presentation: a case report.},
journal = {Journal of medical case reports},
volume = {20},
number = {1},
pages = {},
pmid = {42608702},
issn = {1752-1947},
mesh = {Humans ; Male ; Aged ; Atrophy ; Magnetic Resonance Imaging ; *Cerebral Cortex/pathology/diagnostic imaging ; *Neurodegenerative Diseases/diagnostic imaging/psychology ; Electroencephalography ; Alzheimer Disease ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome most commonly associated with atypical Alzheimer's disease. It is characterized by progressive visuospatial and visuoperceptual deficits with relative sparing of memory and language in early stages. Diagnosis is frequently delayed or missed due to clinical heterogeneity, subtle early symptoms, and limited sensitivity of routine cognitive screening tools. Psychiatric symptoms may further obscure the underlying neurological disorder. This case highlights the diagnostic challenges posed by PCA presenting in the context of prominent psychiatric symptoms, combined with a rapid clinical decline.

CASE PRESENTATION: A 68-year-old white Danish male presented with suicidal ideation and was initially admitted to a psychiatric ward. He had a remote history of a suicide attempt and a family history of suicide but no known neurodegenerative disease. Within a short period, severe cognitive and functional impairment became evident, dominated by visuospatial deficits, apraxia, simultanagnosia, optic ataxia, and features of Gerstmann and Balint syndromes, with relative preservation of memory and language. Neuroimaging revealed marked posterior cortical atrophy and parieto-occipitotemporal hypometabolism with sparing of the posterior cingulate cortex. Cerebrospinal fluid analysis showed mildly reduced amyloid-β1-42 and markedly elevated neurofilament light chain levels. Electroencephalography demonstrated focal posterior slowing without epileptiform activity. Extensive evaluation excluded autoimmune, epileptic, metabolic, and prion-related causes. Based on the clinical syndrome, characteristic neuroimaging findings, and supportive CSF biomarkers, a diagnosis of posterior cortical atrophy likely related to underlying Alzheimer's disease pathology was made. Disease-specific treatment was discussed but not initiated due to patient preference.

CONCLUSIONS: This case illustrates how posterior cortical atrophy may be overlooked, particularly when psychiatric symptoms dominate the initial presentation. It underscores the importance of considering neurodegenerative disorders in older patients with atypical psychiatric presentations or unexplained functional decline. Early recognition of PCA is crucial for accurate diagnosis, appropriate counseling, and tailored supportive care.},
}

Humans
Male
Aged
Atrophy
Magnetic Resonance Imaging
*Cerebral Cortex/pathology/diagnostic imaging
*Neurodegenerative Diseases/diagnostic imaging/psychology
Electroencephalography
Alzheimer Disease
Neuropsychological Tests

@article {pmid42608731,
year = {2026},
author = {Long, W and Yuan, M and Wang, S and Tan, X and Gao, LC},
title = {The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.},
journal = {Translational neurodegeneration},
volume = {15},
number = {1},
pages = {},
pmid = {42608731},
issn = {2047-9158},
support = {2025JJ80178//the Hunan Provincial Natural Science Foundation of China/ ; kq2502334//the Changsha Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitophagy/physiology ; *Inflammasomes/metabolism ; *Parkinson Disease/pathology/metabolism ; *Alzheimer Disease/pathology/metabolism ; Animals ; Mitochondria/metabolism/pathology ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.},
}

Humans
*Mitophagy/physiology
*Inflammasomes/metabolism
*Parkinson Disease/pathology/metabolism
*Alzheimer Disease/pathology/metabolism
Animals
Mitochondria/metabolism/pathology
alpha-Synuclein/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid42609487,
year = {2026},
author = {Huang, J and Li, X and Zhou, K and Liu, B and Wei, Y and Guo, H and Wei, S and Xu, S and Liu, Y and Huang, J and Deng, D and Liang, L},
title = {High-frequency taVNS modulates olfaction-related brain activity in patients with subjective cognitive decline.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1888005},
pmid = {42609487},
issn = {1662-5161},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is considered a high-risk factor for Alzheimer's disease and serves as a critical window of the prevention and treatment. Transcutaneous auricular vagus nerve stimulation (taVNS) has shown therapeutic effects on cognitive impairment, but there is a lack of research on its application in SCD.

PURPOSE: This study aimed to explore the immediate modulatory effects of taVNS at different frequencies on the brain function in patients with SCD.

METHODOLOGY: Seventy SCD and 49 healthy control (HC) were enrolled. Resting-state functional MRI data were collected at baseline and during taVNS with three stimulation conditions: 1 Hz-taVNS, 20 Hz-taVNS, and sham taVNS (staVNS), respectively. Regional homogeneity (ReHo) analysis was used to identify spontaneous neural activity changes in SCD; the abnormal brain regions were then used as seed for subsequent functional connectivity (FC) analysis. In addition, ReHo and FC analyses were performed to assess the immediate modulatory effects of taVNS in SCD.

RESULTS: Compared with HC, SCD showed abnormal ReHo and FC mainly involving olfaction-related brain regions, and the reduced value was positively associated with Shape Trail Test-part B. During taVNS, we found that 20 Hz-taVNS significantly increased ReHo in the bilateral olfactory cortex compared with baseline, and decreased FC between the left medial orbitofrontal cortex and the right precentral and postcentral gyri. No significant ReHo or FC changes were observed during 1 Hz-taVNS and staVNS.

CONCLUSION: These findings suggest that SCD exhibits reduced spontaneous activity and disrupted FC in the olfaction-related brain regions, which may reflect early functional alterations before objective impairment; 20 Hz-taVNS can modulate these cerebral functional abnormalities and may hold potential as a noninvasive neuromodulation strategy in SCD.},
}

@article {pmid42610018,
year = {2026},
author = {Umbria, M and Exposito, J and Gasol, M and Vallano, A},
title = {A regional registry ensures clinical guideline adherence and economic sustainability of Alzheimer's disease treatment: a 12-year population-based study in Catalonia.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1848809},
pmid = {42610018},
issn = {1663-9812},
abstract = {Population-based registries for Alzheimer's disease pharmacological treatment are essential tools for monitoring clinical guideline adherence and health system sustainability. This retrospective observational study analyzes 12 years of real-world data from the Catalan Registry of Pharmacological Treatment of Alzheimer's Disease (RTFMA) between 2012 and 2024. Analyzing a cohort of over 158,000 patients treated with acetylcholinesterase inhibitors or memantine, we found that the treated population increased by 24.5%, reaching 56,874 individuals in 2024. The implementation of a mandatory registration system was associated with high clinical appropriateness, with 81.9% of treatments initiated at recommended moderate stages (GDS 4-5), while only 8.6% began at mild stages. Despite the aging population and the impact of the COVID-19 pandemic-which caused a transient decline in treatment initiations in 2020-the system demonstrated resilience with a full recovery by 2023. Treatment discontinuation was primarily driven by mortality (95% of known reasons), indicating high persistence until end-of-life. From an economic perspective, Alzheimer's therapies represented a stable 1.9% of the total public pharmaceutical budget in 2023, reflecting effective cost containment through generic drug use. These findings suggest that a centralized, guideline-linked registry optimizes patient selection and maintains the economic viability of Alzheimer's care, providing a robust framework for the future integration of high-cost disease-modifying therapies.},
}

@article {pmid42610081,
year = {2026},
author = {Eldehna, WM and El-Damasy, AK and Lim, J and Hefny, SM and Al-Warhi, T and Elgohary, AS and El-Hamaky, AA and Paik, MJ and Elnagar, MR and Elimam, DM and Omar, YM and Kim, H and Tawfik, HO},
title = {Quinazolinone-triazole hybrids as multi-target-directed ligands for Alzheimer's disease: discovery of potent and selective MAO-B inhibitors with cholinesterase modulating activity.},
journal = {RSC advances},
volume = {},
number = {},
pages = {},
pmid = {42610081},
issn = {2046-2069},
abstract = {A new series of quinazolinone-triazole hybrids (QTHs, 5a-n) was designed, synthesized, and evaluated as potential multi-target-directed ligands for Alzheimer's disease. All synthesized compounds were screened against human monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). The obtained results revealed pronounced selectivity toward MAO-B, with IC50 values ranging from 0.65 to 7.51 µM, while exhibiting negligible MAO-A inhibition (IC50 > 40 µM). Compounds 5a, 5d, 5g, 5h, and 5m emerged as the most potent and selective MAO-B inhibitors and were subsequently evaluated for inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among them, compound 5h displayed the most favorable biological profile, showing potent inhibition of MAO-B (IC50 = 0.65 µM), AChE (IC50 = 0.084 µM), and BuChE (IC50 = 0.667 µM). In silico ADMET analysis indicated acceptable drug-like properties for the lead compounds. Furthermore, molecular docking studies against MAO-B and AChE revealed favorable binding interactions, while a 500 ns molecular dynamics simulation confirmed the stability of the 5h-MAO-B complex. Collectively, the present findings identify compound 5h as a promising lead candidate and highlight quinazolinone-triazole hybrids as attractive scaffolds for the development of selective MAO-B inhibitors with additional cholinesterase inhibitory activity for Alzheimer's disease treatment.},
}

@article {pmid42610650,
year = {2026},
author = {Hiruta, Y and Jin, Z and Adachi, M and Amer, L and Tjokro, NO and Trujillo, DF and Potempa, J and O'Donoghue, AJ and Chen, C and Jokerst, JV},
title = {Protease-Triggered Chromogenic Release From Peptide-Modified Calcium Carbonate Microspheres Enables Colorimetric Detection of Porphyromonas gingivalis Activity.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77102},
pmid = {42610650},
issn = {2198-3844},
support = {//Shiley Foundation/ ; //National Nanotechnology Coordinated Infrastructure/ ; ECCS-2025752//National Science Foundation/ ; 22KK0234//Promotion of Joint International Research (Fostering Joint International Research/ ; 21K06495//Promotion of Joint International Research (Fostering Joint International Research/ ; //Japan Society for the Promotion of Science/ ; //Fukuzawa Memorial Fund/ ; },
abstract = {Porphyromonas (P.) gingivalis is a Gram-negative anaerobic bacterium with exceptionally high pathogenicity among periodontal pathogens. It is associated not only with periodontal disease but also with various systemic diseases, including Alzheimer's disease, rheumatoid arthritis, and atherosclerosis. Therefore, early detection of this bacterium is crucial for enabling subsequent treatment and prevention of such conditions. Herein, we report a chromogenic release-based assay system utilizing calcium carbonate microspheres and a dye-labeled peptide that is selectively cleaved by an Arg-specific protease called gingipain (RgpB) that is secreted by P. gingivalis. By utilizing the reactive anhydride functional groups of poly(isobutylene-alt-maleic anhydride), we simultaneously achieved the conjugation of the dye-labeled peptide and its immobilization onto calcium carbonate microspheres. Through optimization of the peptide sequence and the surface modification density on calcium carbonate microspheres, the assay of RgpB detection with the absorbance of supernatant exhibited a low limit of detection of 0.25 nM, as well as high storage stability and selectivity for P. gingivalis. The measurements obtained with this assay system for clinical gingival crevicular fluid samples showed a high correlation (Pearson's r = 0.79) with qPCR results. This assay system offers an on-site, visual means to monitor P. gingivalis activity without requiring specialized instrumentation.},
}

@article {pmid42611034,
year = {2026},
author = {Dodart, CA},
title = {The locus coeruleus gateway hypothesis: Noradrenergic integrity as a candidate determinant of amyloid-β clearance efficiency in anti-amyloid immunotherapy for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261474020},
doi = {10.1177/13872877261474020},
pmid = {42611034},
issn = {1875-8908},
abstract = {Anti-amyloid immunotherapies (lecanemab, donanemab) produce statistically significant but clinically modest slowing of decline in early Alzheimer's disease (AD), with substantial inter-individual response variability that current covariates-antibody titer, baseline amyloid load, apolipoprotein E ε4 (APOE4) status, or tau burden-leave largely unexplained. We propose that a systematically unmeasured upstream variable contributes to this variability: the structural integrity of the locus coeruleus (LC), the principal source of brain norepinephrine (NE), framed as a candidate determinant of amyloid-β (Aβ) clearance efficiency rather than of overall clinical outcome. This hypothesis paper synthesizes three peer-reviewed lines of evidence and derives a hierarchy of falsifiable predictions; no new data are reported. First, tau pathology initiates in LC neurons before any cortical structure, reducing NE output from the earliest preclinical stage. Second, NE governs two complementary Aβ-clearance pathways: glymphatic flow, via aquaporin-4 dynamics driven by slow LC oscillations during non-REM sleep, and microglial phagocytosis, via β2-adrenergic receptor signaling. Third, in Parkinson's disease, the DTI-ALPS index mediates the relationship between LC integrity on neuromelanin-sensitive MRI and cognition. We term this the Locus Coeruleus Gateway Hypothesis (LCGH). Its mediation chain is testable now in ADNI, which holds research-grade diffusion-tensor imaging; its treatment-response prediction requires immunotherapy cohorts that acquire such imaging, not the existing CLARITY-AD or TRAILBLAZER-ALZ 2 archives, whose safety MRI used diffusion-weighted, not tensor, sequences. We state explicitly that Aβ clearance is only one contributor to clinical benefit, and that the LCGH predicts pharmacodynamic efficiency, not that NE restoration treats AD.},
}

@article {pmid42601176,
year = {2026},
author = {Koh, H and Choi, S and Sung, JE},
title = {Verb-Semantic Feature Analysis for Alzheimer's Dementia in a verb-final language: evidence from Korean.},
journal = {Neuropsychological rehabilitation},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/09602011.2026.2715712},
pmid = {42601176},
issn = {1464-0694},
abstract = {This study examined the effects of Verb-Semantic Feature Analysis (Verb-SFA) on verb naming, noun retrieval, sentence comprehension, and discourse production in individuals with Dementia of the Alzheimer's Type (DAT). Given the lexical-semantic degradation characteristic of DAT and the central role of verbs in Korean, a verb-final language, this study evaluated whether Verb-SFA facilitates treatment, near-transfer, and far-transfer effects. Three male participants, aged 60 or older with 16 years of education, completed 17 sessions: pre-treatment (4 sessions), treatment (10 sessions), and post-treatment (3 sessions). Treatment effects were assessed using 45-item probe sets derived from the Korean Item Selection Naming Test. Results showed significant improvement in naming accuracy for treated verbs, with a robust interaction between treatment sessions and treated items. No significant near-transfer effects were found for untreated verbs in the probe set or on the Action Naming Test. However, significant near-transfer effects were observed for noun retrieval on the Korean-Boston Naming Test, although verbal fluency tasks showed no improvement. Far-transfer effects emerged in sentence comprehension, suggesting strengthened verb-semantic processing supports higher-level linguistic abilities. No measurable gains were observed in discourse production. Overall, Verb-SFA treatment enhanced verb naming and sentence comprehension in individuals with DAT.},
}

@article {pmid42602177,
year = {2026},
author = {Azimzadeh, M and Ababzadeh, S and Kahaki, AG and Babaei, SMH and Seyedebrahimi, R and Farsani, ME},
title = {The Gut-Brain Axis in Neurodegeneration: Mechanistic Links Between Dysbiosis and Neuropathology.},
journal = {Iranian journal of pathology},
volume = {21},
number = {4},
pages = {507-522},
pmid = {42602177},
issn = {1735-5303},
abstract = {BACKGROUND & OBJECTIVE: The gut-brain axis is essentially a two-way communication system that physically connects the brain and the intestinal tract. The connection is mediated through a series of pathways, including neural, endocrine, and immune pathways. Gut dysbiosis, which is explained as an imbalance in the microbial community, has been linked to the causation of various neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the pathological mechanisms in the brain are only partially known. The present review outlines the process of gut dysbiosis and neurodegeneration, detailing the roles of protein aggregation, neuroinflammation, barrier disruption, and neuroglial dysfunction. Then, extending the comparison to a range of neurodegenerative diseases, we discuss the possibility of common pathway therapeutics and actual microbiome-based treatment options planning from the standpoint of microbiome-directed interventions.

CONTENT/FINDINGS: Gut dysbiosis triggers a definable cascade, starting with the disruption of the intestinal barrier and increased permeability (leaky gut), which allows bacterial products (lipopolysaccharides, bacterial amyloids) and pro-inflammatory cytokines to enter systemic circulation. Such peripheral changes weaken the blood-brain barrier and thus allow these factors to access the CNS, where they lead to neuroglial dysfunction (microglial priming, astrocytic reactivity, and oligodendrocyte injury) by disruption of glial homeostasis. CNS glial cell malfunction leads to the development of proteinopathies characteristic of each disease: amyloid and tau hyperphosphorylation in Alzheimer's disease through BACE1 upregulation and kinase activation; synuclein in Parkinson's disease via molecular mimicry, oxidative stress, and impaired clearance; and demyelination in multiple sclerosis through oligodendrocyte apoptosis. Oral bacteria such as Porphyromonas gingivalis aggravate this inflammatory loop through the direct invasion of the CNS and proteolytic cleavage of amyloid and tau. The vagus nerve is yet another pathway through which gut-derived inflammatory signals and pathological synuclein can be transmitted to the brain.

CONCLUSION: The gut microbiome is more than just a correlate of neurodegeneration; it actively promotes neurodegenerative diseases through pathways that can be mechanistically defined. Microbiome-targeted interventions such as dietary changes, precision probiotics, fecal microbiota transplantation, and anti-inflammatory agents offer a measure of hope for changing these pathological processes. Future studies need to be directed at determining the time sequence of cause and effect, finding dependable microbiota-based biomarkers, and formulating tailored strategies that can account for individual microbial composition variability, genetic susceptibility, and environmental exposures. A deeper understanding of the gut-brain axis from this mechanistic perspective could eventually lead to the prevention or postponement of neurodegeneration.},
}

@article {pmid42602264,
year = {2026},
author = {Tarbiat, S and Kantarci-Carsibasi, N},
title = {Dual inhibitory potential of N-methylcytisine against GSK-3β and AChE: implications for Alzheimer's disease treatment.},
journal = {Open life sciences},
volume = {21},
number = {1},
pages = {20251363},
pmid = {42602264},
issn = {2391-5412},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and irreversible cognitive decline. Glycogen synthase kinase 3β (GSK-3β) is significant in tau hyperphosphorylation and neurodegeneration. The cholinergic hypothesis of AD links cognitive impairment to reduced synaptic acetylcholine (ACh). Increased acetylcholinesterase (AChE) activity exacerbates this issue. To search for a potential dual GSK-3β/AChE inhibitor, we focused on N-methylcytisine. This natural cytisine-derived alkaloid has not been studied for its various biological effects on the prevention of AD. The in vitro results indicated that N-methylcytisine displayed promising activity against GSK-3β and AChE with IC50 values of 11 and 22.7 µM, respectively. GSK-3β kinetic study according to the varying substrate or ATP concentrations at different N-methylcytisine levels revealed mixed-type inhibition. The results of the integrated in silico workflow indicate that N-methylcytisine exhibited favorable binding to AChE (docking score -9.6 kcal/mol; MM-GBSA -70.2 kcal/mol), comparable to the reference inhibitor galantamine (-10.8 kcal/mol; -70.6 kcal/mol). In contrast, its interaction with GSK-3β was more moderate (-5.3 kcal/mol; -50.3 kcal/mol) relative to staurosporine (-8.5 kcal/mol; -82.6 kcal/mol), consistent with its smaller scaffold. Overall, the results support a flexible, mixed-type interaction profile and highlight N-methylcytisine as a promising dual-acting candidate for Alzheimer's disease.},
}

@article {pmid42602524,
year = {2026},
author = {Dwivedi, AK and Imbimbo, BP and Abanto, J and Espay, AJ},
title = {Comparison of double-blind and open-label decline rates in lecanemab and donanemab trials in Alzheimer's disease.},
journal = {BMJ neurology open},
volume = {8},
number = {2},
pages = {e001649},
pmid = {42602524},
issn = {2632-6140},
abstract = {BACKGROUND: Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer's disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias.

METHODS: We simulated longitudinal Clinical Dementia Rating-Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data.

RESULTS: Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity.

CONCLUSIONS: Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.},
}

@article {pmid42602880,
year = {2026},
author = {Murugadoss, K and Venkatakrishnan, AJ and Soundararajan, V},
title = {GLP-1-based incretin therapy is associated with lower incident Alzheimer's disease and cardiorenal events in adults with documented neuropsychiatric, cognitive, or sensory risk.},
journal = {Biology methods & protocols},
volume = {11},
number = {1},
pages = {bpag043},
pmid = {42602880},
issn = {2396-8923},
abstract = {Alzheimer's disease (AD) develops over years, creating an opportunity for interventions that target modifiable risk factors before the onset of clinical dementia. Here we applied a federated electronic health record (EHR) system encompassing over 29 million de-identified patients toward a target-trial emulation framework involving 153,412 adults aged 50 years or older with at least one documented AD risk factor. New users of glucagon-like peptide-1 (GLP-1)-based incretin therapy were compared with new users of non-GLP-1 antidiabetic medications after a 12-month washout, with 1:1 propensity-score matching on 30 baseline variables and additional exact matching on index year of therapy initiation and 5-year age band. In the primary matched cohort, 28,901 patients per arm, incretin initiation was associated with lower first recorded AD diagnosis (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.29-0.73, q = 0.003), all-cause dementia (HR 0.66 [0.55-0.79], q < 0.001), and all-cause mortality (HR 0.46 [0.37-0.58], q < 0.001), with directionally-lower Mild Cognitive Impairment (HR 0.76 [0.61-0.94], q = 0.135) and Alzheimer's-related medication initiation (HR 0.82 [0.65-1.03], q = 0.217). The AD diagnosis mitigation signal was independently reproduced for semaglutide (HR 0.56; N = 23,675 per arm; q = 0.02), with the directionally consistent tirzepatide point estimate (HR 0.60) not reaching significance. GLP-1 RA initiation was also associated with substantially lower (all q < 0.001) incidence of heart failure (HR 0.50 [0.45-0.55]), cardiomyopathy (HR 0.38 [0.31-0.47]), major adverse cardiovascular events (HR 0.74 [0.67-0.82]), acute kidney injury (HR 0.67 [0.67-0.74]), and chronic kidney disease (HR 0.68 [0.62-0.75]). Negative-control outcomes showed no significant separation (all q > 0.45), including allergic rhinitis (HR 0.96 [0.87-1.07]), hemorrhoids (HR 1.07 [0.95-1.21]), and inguinal hernia (HR 1.39 [0.89-2.18]). Stricter two-code ICD definitions supported lower first recorded AD diagnosis in the incretin arm (HR 0.51 [0.29-0.89], q = 0.018) and lower first recorded all-cause dementia diagnosis (HR 0.68 [0.54-0.85], q = 0.003). In 12-month landmark analyses among semaglutide initiators, ≥5% weight-loss responders had lower 3-year AD cumulative incidence than non-responders after matching (0.07% vs. 0.40%; incidence ratio 5.76; P = .036), although this was not significant in the hazard-ratio model (HR 0.54, P = .39). Sustained-dose stratification showed no comparable gradient (high-dose vs. low-dose 0.30% vs. 0.14%; HR 2.77; P = .38), with ≤12 AD events per group. The weight-loss-specific pattern did not extend to all-cause dementia: weight-loss responders and non-responders had similar 3-year cumulative incidence (1.54% vs. 1.70%; HR 0.87, P = .53). Initiation of GLP-1 receptor agonist therapy in adults with documented AD risk factors was associated with lower recorded incidence of AD, dementia, mortality, and multiple cardiovascular and renal outcomes in this observational target-trial emulation. These findings support the hypothesis that earlier incretin therapy may contribute to AD risk modification through upstream cardiometabolic pathways, while prospective randomized prevention studies will be required to determine causality, underlying biological mechanisms, and optimal treatment timing.},
}

@article {pmid42603243,
year = {2026},
author = {Anwer, T and Verma, A and Asiri, A and Alaklobie, M and Albaqami, A and Alshahrani, F and Aly, K and Sharma, M and Siddiqui, S and Alam, N and Alam, MF},
title = {Restoration of Neuronal Metabolism and Memory in Alzheimer's Disease by Reprogramming the Exosomal microRNA Network.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {3},
pages = {},
pmid = {42603243},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *MicroRNAs/metabolism/genetics ; *Exosomes/metabolism/genetics ; Animals ; *Neurons/metabolism ; Neuronal Plasticity ; *Memory ; },
abstract = {Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics
*MicroRNAs/metabolism/genetics
*Exosomes/metabolism/genetics
Animals
*Neurons/metabolism
Neuronal Plasticity
*Memory

@article {pmid42603633,
year = {2026},
author = {Choi, HS and Jeon, SH and Liu, H and Kim, M and Yu, JS and Yoo, SS and Son, DJ and Han, SB and Yeo, IJ and Lim, SC and Hong, JT},
title = {p53 deficiency increases vulnerability to chronic stress-induced anxiety- and depression-like behaviors: Role of calcium dysregulation and BDNF signaling.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116437},
doi = {10.1016/j.bbr.2026.116437},
pmid = {42603633},
issn = {1872-7549},
abstract = {The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53[-/-]) mice and wild type mice. In p53[-/-] mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53[-/-] mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53[-/-] mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53[-/-] mice, and corticosterone-treated primary neuronal cells from p53[-/-] mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.},
}

@article {pmid42604096,
year = {2026},
author = {Bayly, H and Salvati, L and Lenio, S and Mez, J and Alosco, ML and Tripodis, Y},
title = {Evaluating inclusion of continuous multivariable cognitive scores for operational enrichment of preclinical Alzheimer's disease trials: a retrospective emulation study.},
journal = {JAR life},
volume = {15},
number = {},
pages = {100081},
pmid = {42604096},
issn = {2534-773X},
support = {R01 AG053509/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG073235/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; R01 AG056258/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG045571/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; U24 RR021382/RR/NCRR NIH HHS/United States ; U19 AG073153/AG/NIA NIH HHS/United States ; R01 AG043434/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; R01 DC008552/DC/NIDCD NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG058724/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; I01 RX001534/RX/RRD VA/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; S10 OD026738/OD/NIH HHS/United States ; R35 AG072262/AG/NIA NIH HHS/United States ; R01 AG077444/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; U24 AG067418/AG/NIA NIH HHS/United States ; R01 AG068338/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; R01 AG062276/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R01 AG053993/AG/NIA NIH HHS/United States ; R01 AG067781/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; R01 NS075075/NS/NINDS NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; P30 NS098577/NS/NINDS NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG056531/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; R01 AG021910/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; R01 AG061788/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; I21 RX001381/RX/RRD VA/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; U19 NS120384/NS/NINDS NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R56 AG045571/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P50 MH071616/MH/NIMH NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG054110/AG/NIA NIH HHS/United States ; R01 AG052560/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Prevention trials for Alzheimer's Disease face significant challenges due to the slow and uncertain rate of cognitive decline in asymptomatic, amyloid-positive individuals. Biomarker positivity alone does not guarantee clinically meaningful progression, often leaving studies underpowered.

OBJECTIVES: Evaluate model-based operational trial enrichment within an amyloid-positive, cognitively normal subgroup.

METHODS: Trained on a small cohort from the National Alzheimer's Coordinating Center (N = 113), with external validation using baseline data of a similar small cohort from the Alzheimer's Disease Neuroimaging Initiative (N = 161). Gradient-boosted decision trees estimated progression risk and projected power under alternative enrollment strategies. Predictors included neuropsychological scores, demographics, medical history, and ApoE ε4 genotype. The primary outcome was clinical progression to cognitive impairment within 1- and 3-year follow-up windows.

RESULTS: In the independent testing set, the model successfully increased the effective prevalence of the outcome. The Positive Predictive Value for the 1-year window was 0.27 (a 35% relative increase over the 0.20 baseline prevalence) and 0.43 for the 3-year window (a 23% relative increase over the 0.35 baseline). Power simulations for an emulated trial (N = 500) demonstrated that this enrichment strategy consistently increased statistical power, potentially reducing the required sample size to achieve 80% power by up to 32% for small treatment effect sizes.

CONCLUSIONS: This operational methodology functions as a screening filter to optimize event rates within a highly specific, preselected trial population.},
}

@article {pmid42605027,
year = {2026},
author = {Duijkers, S and Ter Huurne, DBG and Blom, M and Bodde, HE and Dobbe, JHM and Van der Flier, W and Jansen, WJ and Olde Rikkert, M and Papma, JM and Verhey, FRJ and Ramakers, IHGB},
title = {Current Practice and Long-Term Developments in Multidisciplinary Dutch Memory Clinics.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261478290},
doi = {10.1177/08919887261478290},
pmid = {42605027},
issn = {1552-5708},
abstract = {ObjectivesMemory Clinics (MCs) have a central role in multidisciplinary diagnostics and care of cognitive disorders and dementia. This study describes current clinical practice and developments of Dutch MCs since their start in 1986.MethodsA survey was sent to all Dutch hospital-based MCs in 1998, 2004, 2009, 2017 and 2023. Topics included: organization, patient characteristics, scales and questionnaires, neuropsychological assessment, additional assessments, novel biomarkers, disclosure of diagnosis and treatment. 74 out of the total of 89 MCs completely or partially filled out the questionnaire.ResultsThe number of MCs increased to 89. The number of patients seen increased substantially (per MC/year: 1998: 130; 2023: 324; total: 1998: 1560; 2023: 28,848). The proportion of patients diagnosed with dementia decreased from 80% in 1998 to 47% in 2023. Most commonly available assessments were neuroimaging (100%), routine laboratory testing of blood (98%) and neuropsychological assessment (NPA; 98%). Thirty-one percent indicated infrastructure needed to be changed before prescribing monoclonal antibody treatments for Alzheimer's disease.ConclusionsMCs showed substantial development in number, number of patients and geographical distribution within the country. Nowadays, MCs are central care facilities for the timely and multidisciplinary diagnosis and treatment of people with cognitive disorders and dementia.},
}

@article {pmid42605139,
year = {2026},
author = {Javed, MN and Khan, SM and Mustafa, S and Mujtaba, A and Amin, H and Azhar, N and Hameed, A and Zayed, A and Khalid, M and Hussain, JM},
title = {Gantenerumab for Early Alzheimer's Disease: An Updated Systematic Review and Meta-Analysis.},
journal = {Brain and behavior},
volume = {16},
number = {8},
pages = {e71643},
doi = {10.1002/brb3.71643},
pmid = {42605139},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Randomized Controlled Trials as Topic ; Amyloid beta-Peptides ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options. Gantenerumab, a β-amyloid-targeting monoclonal antibody, has shown mixed clinical results. With new trial data available, this updated systematic review and meta-analysis re-evaluates its efficacy and safety in early AD.

METHODS: Registered on PROSPERO (CRD420251082463) under PRISMA guidelines, we searched PubMed, Cochrane Library, and Google Scholar from inception to October 2025 for randomized trials in early AD comparing gantenerumab with placebo. A random-effects model assessed pooled outcomes with heterogeneity (I[2]) and sensitivity analyses. Additionally, meta-regression and certainty of evidence using Gradepro were performed. Risk of bias was evaluated using the Cochrane tool. An Institutional Review Committee (IRC) and its Ethical Review Board (ERB) approval was not required.

RESULTS: Six trials (3103 participants: 1718 gantenerumab; 1385 placebo) were included. Gantenerumab showed no significant effect on CDR-SB (MD = -0.07; 95% CI: -0.34-0.20; p = 0.62; I[2] = 16%) but produced small improvements in FAQ (MD = -0.73; 95% CI: -1.30 to -0.17; p = 0.01; I[2] = 0%) and Amyloid-PET score (MD = -45.67; 95% CI: -88.09 to -3.24; p = 0.03; I[2] = 99%). While significant statistical improvement was seen in the ADAS-Cog13 score (MD = -0.95; 95% CI: -1.76 to -0.13; p = 0.02; I[2] = 0%), the effect sizes for both FAQ and ADAS-Cog13 fell below established MCID thresholds. MMSE and ADCS-ADL showed no significant differences. Safety analysis revealed higher risks of ARIA-E (RR = 5.51), ARIA-H (RR = 1.73), and injection site reactions (RR = 2.15), with no differences in other adverse events.

CONCLUSION: Gantenerumab significantly reduces amyloid and statistically improves select functional (FAQ) and cognitive (ADAS-Cog13) measures in early AD; however, these changes remain below accepted MCID thresholds, indicating a lack of true clinical meaningfulness. Combined with its failure to enhance global cognition and an increased ARIA risk, routine clinical use is not supported.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Randomized Controlled Trials as Topic
Amyloid beta-Peptides

@article {pmid42606634,
year = {2026},
author = {Cheng, L and Gong, P and Su, X and Fang, Y and Wang, T},
title = {miR-584-5p suppresses Aβ1-42-induced apoptosis in Alzheimer's disease cell model via targeting of HDAC1.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42606634},
issn = {2240-2993},
abstract = {BACKGROUND: Alzheimer's disease (AD) represents a profoundly detrimental neurodegenerative disorder, and early diagnosis coupled with effective treatment remains a major clinical challenge. MicroRNAs (miRNAs) have emerged as key regulators associated with pathological processes in AD.

AIM: This study aimed to explore the expression pattern and the likely diagnostic value of miR-584-5p in AD, as well as its molecular mechanism of action in regulating β-amyloid (Aβ)-induced apoptosis.

METHODS: Peripheral blood samples from 90 AD patients and age- and sex-matched controls were examined using RT-qPCR. Correlation analyses of miR-584-5p expression with key AD biomarkers (Aβ42, tTau, pTau) were performed in AD patients. Following exposure to 5 µM Aβ1-42, SH-SY5Y cells were employed in subsequent functional experiments. Bioinformatics analysis, a dual-luciferase reporter assay, and negative correlation analysis of plasma samples were conducted to verify the target gene of miR-584-5p.

RESULTS: miR-584-5p was significantly downregulated in AD patients, and its expression correlated with Aβ42 (r = 0.665), total tau (tTau, r = -0.642), phosphorylated tau (pTau, r = -0.576), and Mini-Mental State Examination (MMSE) scores (r = 0.618), yielding an AUC of 0.864 in this single-center cohort. miR-584-5p overexpression inhibited 5 µM Aβ1-42-induced apoptosis in SH-SY5Y cells, an effect that was reversed by concurrent HDAC1 overexpression. Mechanistically, by targeting HDAC1, miR-584-5p modulates p53 acetylation and the Bcl-2/Bax pathway at the protein level.

CONCLUSIONS: miR-584-5p exerted neuroprotective effects via the miR-584-5p/HDAC1 axis, offering new insights into AD pathogenesis and suggesting this axis as a candidate for further preclinical investigation.},
}

@article {pmid42606694,
year = {2026},
author = {Jaiswal, C and Singh, I and Singh, AK},
title = {Fisetin Attenuates Amyloid-Beta-Induced Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells: Integrating In Silico Target Prediction and In Vitro Validation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {9},
pages = {e71076},
doi = {10.1002/jbt.71076},
pmid = {42606694},
issn = {1099-0461},
support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; },
mesh = {Humans ; Flavonols ; *Amyloid beta-Peptides/toxicity/metabolism ; *Flavonoids/pharmacology/chemistry ; *Neuroblastoma/metabolism/pathology/drug therapy ; Cell Line, Tumor ; *Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; },
abstract = {The accumulation of amyloid beta (Aβ) and tau tangles in the brain leads to Alzheimer's disease (AD). Fisetin, a natural flavonoid, is an antioxidant molecule, and its neuroprotective effects are not clearly understood. Therefore, attempts have been made to evaluate the neuroprotective effects of fisetin using in silico methods and an Aβ1-42-induced neurotoxicity model in human neuroblastoma SH-SY5Y cells. In silico studies demonstrated that fisetin binds strongly and with high stability to different proteins, such as ULK1 (autophagy marker), p21 (senescence/cell cycle marker), and synaptophysin (synaptic marker), which are responsible for maintaining brain health and are implicated in AD. Moreover, Aβ1-42 was also found to bind to these protein targets, indicating that Aβ1-42 and fisetin both target common binding sites. In vitro studies on SH-SY5Y cells further confirmed that fisetin promotes cell survival under the toxic effects of Aβ1-42. It reduced oxidative stress and restored the activities of ion channels, which were impaired by Aβ1-42 treatment. Fisetin increased antioxidant defense and restored the activity of molecules that control brain signals. Overall, fisetin acts on multiple targets to protect neurons by reducing oxidative damage, supporting ion channel activity, and inducing the autophagy process.},
}

Humans
Flavonols
*Amyloid beta-Peptides/toxicity/metabolism
*Flavonoids/pharmacology/chemistry
*Neuroblastoma/metabolism/pathology/drug therapy
Cell Line, Tumor
*Peptide Fragments/toxicity
*Neuroprotective Agents/pharmacology
Oxidative Stress/drug effects
Molecular Docking Simulation

@article {pmid42607896,
year = {2026},
author = {Li, X and Chen, Z and Guan, J and Yu, H and Wang, J},
title = {Oral Administration of Melatonin Modulates Macrophage Polarization via Modulating the Vegf Signaling Pathway and Ameliorates Alzheimer's Disease in APP/PS1 Mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {112088},
doi = {10.1016/j.brainresbull.2026.112088},
pmid = {42607896},
issn = {1873-2747},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with a global prevalence, currently lacking effective treatments and posing a major public health challenge due to the burden it places on healthcare systems while affecting millions of people. Melatonin is a hormone with considerable potential for treating various neurodegenerative disorders, including AD. The mechanisms responsible for melatonin's therapeutic benefits in Alzheimer's disease (AD) require further elucidation. This study was designed to investigate the mechanisms by which melatonin exerts its effects in APP/PS1 mice.

METHODS: The Morris water maze was used to assess the performance of melatonin-treated APP/PS1 mice. Haematoxylin&Eosin and Nissl staining were conducted to observe the integrity of hippocampal neurons. Transcriptomic sequencing of hippocampal tissue was performed to identify differentially expressed genes, which were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Immunofluorescence analysis was used to detect the levels of Cd16, Cd32, Cd68 and Cd206 in APP/PS1 mice. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunohistochemistry were employed to validate the relative expression of Vegf, Flt1, and Kdr proteins.

RESULTS: In the Morris water maze, melatonin-treated APP/PS1 mice demonstrated a marked increase in platform crossings. Improved neuronal integrity in the hippocampus was observed through Haematoxylin&Eosin and Nissl staining. Transcriptomic sequencing of hippocampal tissue revealed 295 differentially expressed genes, which were significantly associated with 1091 GO terms and 30 KEGG pathways. Immunofluorescence analysis indicated that melatonin treatment notably reduced Cd16 and Cd32 levels while elevating Cd68 and Cd206 in APP/PS1 mice. Subsequent analyses via RT-qPCR, immunoblotting, and immunohistochemistry validated the increased relative expression of Vegf, Flt1, and Kdr proteins.

DISCUSSION: Melatonin attenuates AD pathogenesis in APP/PS1 mice by promoting macrophage polarization via the Vegf signaling pathway, revealing a novel mechanism for AD prevention and treatment.},
}

@article {pmid42608531,
year = {2026},
author = {Wu, YL and Xu, QQ and Qin, ZH and Wu, X and Hu, Z and Yang, W and Ren, PY and Tian, YY and Lin, ZX and Xian, YF},
title = {Oxyberberine-nanoparticle attenuates the cognitive deficits in a transgenic mouse model of Alzheimer's disease via modulating gut microbiota through suppressing CXCL10/CXCR3 pathway.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42608531},
issn = {1745-7254},
abstract = {Oxyberberine (OBB) has good potential neuroprotective effects. However, the poor water solubility of OBB poses a challenge to its therapeutic effects. In this study, OBB-hydroxypropyl-β-cyclodextrin (OBB-β-CD) was prepared to increase the water solubility and improve bioavailability of OBB. The neuroprotective effects of OBB-β-CD against AD were investigated using 3×Tg transgenic AD mouse model. OBB-β-CD exhibited dual regulatory capabilities in improving both behavioral deficits and pathological features of AD. OBB-β-CD was more effective than OBB in modulating the amyloid precursor protein (APP) processing and inhibiting the hyperphosphorylation of Tau protein. OBB-β-CD was effective in reducing both the concentration of beta-amyloid 42 (Aβ42) and the deposition of Aβ plaques in 3×Tg mouse models. OBB-β-CD also suppressed neuroinflammation by promoting microglial polarization from an M1-like to an M2-like phenotype. Furthermore, OBB-β-CD restored the gut dysbiosis and inhibited the activation of the C-X-C motif chemokine receptor 3 (CXCR3) and the level of C-X-C motif chemokine ligand 10 (CXCL10) in the brain and colon tissues of 3×Tg mice. Simultaneously, the effect of OBB that suppressed microglial M1 and promoted M2 polarization to improve the neuronal micro-environment was verified in vitro using BV-2 cells. Importantly, OBB-β-CD showed similar anti-AD effects of knockdown of CXCR3 in 3×Tg mice, but no synergistic effects were observed in the shCXCR3 + OBB-β-CD group compared to the shCXCR3 group. Furthermore, the results of molecular docking and surface plasmon resonance (SPR) assay indicated that CXCR3 could bind with OBB. Additionally, the fecal microbiota transplantation (FMT) of fecal microbiota from the OBB-β-CD-treated 3×Tg mice (OBB-β-CD-FMT) significantly alleviated the cognitive deficits in the pseudo-germ-free 3×Tg mice via markedly suppressing the hyperphosphorylation of Tau protein, Aβ level and the activation of CXCR3 in the brain of 3×Tg mice. OBB-β-CD has good potential for further development into a therapeutic agent for AD treatment.},
}

@article {pmid42608660,
year = {2026},
author = {Shinagawa, S and Nagata, T},
title = {Toward Precision Neuropsychiatry of Dementia: Neuropsychiatric Symptoms as Multidimensional Clinical Phenotypes.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {5},
pages = {e70209},
doi = {10.1111/psyg.70209},
pmid = {42608660},
issn = {1479-8301},
support = {24K10690//Japan Society for the Promotion of Science/ ; JP24wm0625505//Japan Agency for Medical Research and Development/ ; },
mesh = {Humans ; *Dementia/psychology/diagnosis ; Phenotype ; *Neuropsychiatry/methods ; *Precision Medicine/methods ; Sleep Wake Disorders ; },
abstract = {Neuropsychiatric symptoms (NPS) are the most clinically consequential manifestations of dementia, yet they are frequently underestimated as secondary behavioural complications. This review introduces a precision neuropsychiatry framework that conceptualises NPS-including apathy, agitation, psychosis, depression, and sleep disturbances-as multidimensional clinical phenotypes. These phenotypes bridge neurodegeneration, biological aging, brain network disruption, psychosocial context, functional decline, and caregiver burden. We trace the conceptual evolution from dementia to neurocognitive disorders, and from behavioural and psychological symptoms of dementia (BPSD) to NPS and mild behavioural impairment (MBI). Precision neuropsychiatry stratifies NPS based on disease background, clinical stage, neural networks, biological aging, physical vulnerability, and psychosocial context to optimise differential diagnosis, prognostic prediction, and targeted interventions. Although conventional symptom-based classification remains practically useful, it must be complemented by biological, functional, and contextual stratification; identical symptom labels often arise from distinct mechanisms and express differently based on personality, life history, environmental mismatch, and available resources. Emerging evidence from MBI, neuroimaging, brain-age paradigms, frailty, neuroinflammation, Alzheimer's disease (AD) biomarkers, and international consensus criteria supports this multidimensional shift. Future research should advance from cross-sectional symptom descriptions toward longitudinal, mechanism-informed, and context-sensitive models to translate these findings into real-world psychogeriatric care.},
}

Humans
*Dementia/psychology/diagnosis
Phenotype
*Neuropsychiatry/methods
*Precision Medicine/methods
Sleep Wake Disorders

@article {pmid42598748,
year = {2026},
author = {Tonietto, M and Silvestri, E and Belder, CRS and Barkhof, F and Fox, NC and Smith, J and Klein, G},
title = {Volume change with gantenerumab: Impact of amyloid-related imaging abnormalities and amyloid removal.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71749},
pmid = {42598748},
issn = {1552-5279},
support = {//F. Hoffmann-La Roche/ ; },
mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; *Amyloid beta-Peptides/metabolism ; *Brain/diagnostic imaging/pathology/drug effects ; Female ; Male ; Magnetic Resonance Imaging ; *Amyloid/metabolism ; White Matter/pathology/diagnostic imaging ; },
abstract = {INTRODUCTION: Amyloid-lowering antibodies are associated with neuroanatomical volume changes. This study aims to disentangle the contributions of amyloid-related imaging abnormalities (ARIA) and amyloid clearance to these changes.

METHODS: Data from the GRADUATE I and II trials of gantenerumab in early Alzheimer's disease were analyzed. Participants were grouped as placebo, gantenerumab-treated without ARIA, or gantenerumab-treated with ARIA.

RESULTS: Gantenerumab treatment was associated with greater parenchymal volume reduction than placebo, with no difference between ARIA and non-ARIA groups. The ARIA group exhibited greater ventricular enlargement which was offset by reduced external cerebrospinal fluid space expansion. Greater amyloid removal correlated with greater volume reduction, although volume changes also occurred in white matter, where amyloid is minimal. Furthermore, the ARIA group showed a flatter relationship between ventricular expansion and clinical decline.

DISCUSSION: ARIA are not associated with long-term parenchymal reduction; rather, they are linked to a fluid shift from the external space to the ventricles. Amyloid removal correlates with parenchymal changes, but white matter changes suggest additional mechanisms beyond local clearance. Neither phenomenon was associated with worse clinical outcomes.

TRIAL REGISTRATION NUMBER: NCT03444870 and NCT03443973.},
}

Humans
*Antibodies, Monoclonal, Humanized/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging/pathology
*Amyloid beta-Peptides/metabolism
*Brain/diagnostic imaging/pathology/drug effects
Female
Male
Magnetic Resonance Imaging
*Amyloid/metabolism
White Matter/pathology/diagnostic imaging

@article {pmid42600000,
year = {2026},
author = {Chae, H and Park, Y and Kim, Y and Yoon, E and Kim, KW and Yoo, S},
title = {Wearable transparent OLED glasses for cognitive stimulation: Enhancing brain connectivity through gamma entrainment.},
journal = {Science advances},
volume = {12},
number = {33},
pages = {eaee5504},
pmid = {42600000},
issn = {2375-2548},
mesh = {Humans ; *Wearable Electronic Devices ; *Cognition/physiology ; *Brain/physiology ; *Gamma Rhythm/physiology ; Cognitive Enhancement ; },
abstract = {Gamma wave entrainment is a promising approach for improving cognitive function, particularly in the early stages of Alzheimer's disease. However, for everyday treatment, a light source system that maintains visibility while delivering effective stimulation is essential for patient comfort and practicality. To address this need, we developed organic light-emitting diode (OLED) glasses with optimized large-area transparent OLEDs for gamma wave entrainment. The optimization involved all layers of the device, including encapsulation, to achieve high luminous transmittance (75%), uniformity (over 90%), and electrical performance, ensuring suitability for wearable applications. Under real-world conditions (see-through visibility and ambient light present), the transparent OLED glasses successfully induced gamma rhythm entrainment, enhancing brain connectivity between the occipital and frontal regions. They also notably reduced visual discomfort and showed a trend of enhanced connectivity compared to nontransparent OLEDs. These results highlight the potential of this noninvasive wearable technology for early cognitive intervention, providing comfortable therapeutic light stimulation.},
}

Humans
*Wearable Electronic Devices
*Cognition/physiology
*Brain/physiology
*Gamma Rhythm/physiology
Cognitive Enhancement

@article {pmid42600466,
year = {2026},
author = {Kumar, N and Khan, I and Singh, J and Kumar, K and Kushwaha, VK and Ojha, S and Raman, SK and Shankar, G},
title = {Recent developments in donepezil-based hybrid molecules as multi-target therapeutics for Alzheimer's disease: A paradigm shift beyond symptomatic treatment.},
journal = {Bioorganic chemistry},
volume = {181},
number = {},
pages = {110361},
doi = {10.1016/j.bioorg.2026.110361},
pmid = {42600466},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder characterized by the gradual loss of cholinergic neurons, leading to cognitive impairment, synaptic dysfunction, and irreversible neuronal degeneration. The multifactorial nature of AD, involving cholinergic deficits, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, and metal dyshomeostasis, has limited the clinical success of single-target therapeutic strategies. Although donepezil (DPZ), a clinically approved acetylcholinesterase (AChE) inhibitor, remains one of the most widely prescribed agents for symptomatic management, it does not alter the underlying neurodegenerative processes. Consequently, DPZ has emerged as an attractive medicinal chemistry scaffold for the development of multi-target-directed ligands (MTDLs) that simultaneously modulate multiple interconnected pathological pathways implicated in AD. This review provides a comprehensive and critically organized overview of recent advances in DPZ-based hybrid molecules, emphasizing rational design strategies, hybridization approaches, structure-activity relationships (SAR), molecular mechanisms, and pharmacological profiles. To facilitate a mechanistic understanding, the reported hybrids are systematically classified according to structural modifications of the indanone moiety, the benzylpiperidine moiety, or simultaneous modification of both pharmacophoric regions. Comparative analysis reveals how scaffold engineering, linker optimization, and strategic incorporation of complementary pharmacophores influence cholinesterase inhibition, anti-amyloid activity, antioxidant capacity, neuroprotection, metal chelation, monoamine oxidase inhibition, and blood-brain barrier permeability. Importantly, this review critically examines the current translational landscape, highlighting that despite encouraging in vitro and in vivo findings, no DPZ-based hybrid has yet advanced to clinical evaluation. Key challenges, including pharmacokinetic optimization, metabolic stability, safety, target engagement, and clinical translatability, are discussed together with future medicinal chemistry directions. Rather than presenting DPZ-based hybrids as established disease-modifying therapies, the available evidence supports their role as promising multifunctional lead compounds and valuable molecular platforms for the rational design of next-generation anti-Alzheimer agents. By integrating emerging SAR trends with critical translational perspectives, this review provides a contemporary framework to guide future development of clinically relevant multifunctional therapeutics for AD.},
}

@article {pmid42600807,
year = {2026},
author = {Fereidouni, A and Nematollahi, S and Mathew, KT and Favennec, V and Liceran, L and Aldenhoff-Kelly, C and Valdivieso, MA and Trent, S and Moradikor, N},
title = {Allosteric modulation of ionotropic and G protein-coupled receptors in Alzheimer's disease: A neuroprotective strategy and therapeutic implications.},
journal = {International journal of biological macromolecules},
volume = {379},
number = {},
pages = {154063},
doi = {10.1016/j.ijbiomac.2026.154063},
pmid = {42600807},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca[2+]-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.},
}

@article {pmid42600874,
year = {2026},
author = {Xiao, J and Lan, Z and Zhang, R and Zhang, J and Hu, Z and Jia, B and Tang, H and Xu, T and Bao, X and Xu, Y and Yu, L and Ji, SL and Zhu, X},
title = {Novel natural inhibitor Rubimaillin targets NLRP3 R167/Y381 to ameliorate inflammatory and neurodegenerative diseases.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {122293},
doi = {10.1016/j.jep.2026.122293},
pmid = {42600874},
issn = {1872-7573},
abstract = {Rubia cordifolia L. is traditionally used in Chinese medicine for treating arthritic and inflammatory conditions by cooling blood and activating circulation. Gouty arthritis, one of the disease models investigated in this study, falls within this traditional anti-arthritic application. This study investigates whether rubimaillin (Rub), a naphthoquinone from Rubia cordifolia, selectively inhibits NLRP3 inflammasome activation and exerts therapeutic effects in relevant disease models. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is a key driver of various inflammatory, metabolic, and neurodegenerative disorders; yet, no clinically approved inhibitor is currently available. Rubia cordifolia L. is a traditional medicinal herb, and Rubimaillin (Rub), a naphthoquinone isolated from this herb, has potential anti-inflammatory properties, but its role and mechanism in regulating NLRP3 activation remain unclear.

AIM OF STUDY: This study aimed to determine whether Rubimaillin (Rub), a naphthoquinone isolated from Rubia cordifolia L., can selectively inhibit NLRP3 inflammasome activation and yield therapeutic effects in relevant NLRP3-driven disease models.

MATERIALS AND METHODS: Mouse primary microglia, bone marrow-derived macrophages (BMDMs), and the human macrophage cell line THP-1 were primed with lipopolysaccharide (LPS) for 3 h, then stimulated with Nigericin or ATP to induce NLRP3 inflammasome assembly and pyroptosis. Caspase-1 activation, apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, interleukin-1β (IL-1β) release, and lactate dehydrogenase (LDH) secretion were quantified. Mutagenesis studies were conducted to identify critical residues required for Rub's binding to NLRP3. The in vivo therapeutic potential of Rub was assessed in three murine models of NLRP3-driven inflammation: LPS-induced sepsis, monosodium urate crystal (MSU)-induced gouty arthritis, and the APP/PS1 double-transgenic Alzheimer's disease (AD) mouse model. Mice received intraperitoneal Rub or vehicle, and disease severity was evaluated by histopathology, cytokine profiling, and behavioral tests.

RESULTS: Rub significantly reduced pyroptosis and IL-1β release in mouse primary microglia, BMDMs, and THP-1 cells in a dose-dependent manner, without affecting Absent in melanoma 2(AIM2) or NLR family CARD domain containing 4 (NLRC4) pathways. Mechanistically, Rub directly bound to NLRP3, thereby blocking the oligomerization of both NLRP3 and ASC, as well as preventing caspase-1 activation and gasdermin D (GSDMD) cleavage. Furthermore, mutagenesis studies identified arginine 167 and tyrosine 381 as critical residues for Rub's binding to NLRP3. In vivo, Rub treatment significantly prolonged survival and attenuated lung injury in the sepsis model, reduced paw swelling and bone erosion in the gout model, and ameliorated cognitive deficits and neuroinflammation in the AD model, respectively.

CONCLUSION: Collectively, these findings demonstrate that Rub selectively targets the NLRP3 inflammasome and exerts therapeutic effects on NLRP3-driven diseases including sepsis, gout, and AD. This study provides a molecular basis for the traditional application of Rubia cordifolia L. and highlights Rub as a promising natural lead compound for the treatment of NLRP3-driven disorders.},
}

@article {pmid42598237,
year = {2026},
author = {Zhang, M and Zhang, Y and Zhang, Z and Jia, X and Lei, S and Bu, N and Wang, Y and Bai, Y and Wang, S},
title = {Effects of mindfulness-based exercise on Parkinson's disease and Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860499},
pmid = {42598237},
issn = {1664-2295},
mesh = {Humans ; *Parkinson Disease/therapy/psychology ; *Alzheimer Disease/therapy/psychology ; *Mindfulness/methods ; *Exercise Therapy/methods ; Yoga ; Qigong ; Tai Ji ; },
abstract = {OBJECTIVE: Currently, there is a lack of robust evidence demonstrating the efficacy of mindfulness-based exercise (MBE) on motor and cognitive outcomes in individuals with Parkinson's disease (PD) and Alzheimer's disease (AD), resulting in the absence of standardized and effective MBE treatment protocols. This systematic review and meta-analysis summarizes the available evidence to evaluate the therapeutic effects of MBE on motor and cognitive function in PD and AD.

METHODS: For two common neurodegenerative diseases, PD and AD, we searched PubMed, Embase, Cochrane Library, and Web of Science to identify studies published from inception to January 30, 2026. Search terms included neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, mindfulness, Tai Chi, yoga, and Qigong. Two independent reviewers assessed the risk of bias of included studies, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-III), Timed Up and Go Test (TUG), Berg Balance Scale (BBS), Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), Parkinson's Disease Sleep Scale (PDSS), Activities of Daily Living (ADL), and Parkinson's Disease Questionnaire-39 (PDQ-39). Data analysis was performed using Review Manager 5.4 software to evaluate effect sizes and 95% confidence intervals (CIs). Heterogeneity tests were conducted to assess differences in treatment effects among Tai Chi, yoga, and Qigong.

RESULTS: We screened 4,576 articles and identified 28 studies that met the inclusion criteria. Of the included studies, 23 focused on PD and 5 on AD. Only 7 reported adequate allocation concealment, and 2 implemented participant blinding. GRADE assessment indicated moderate certainty of evidence for UPDRS-III, TUG, BBS, MoCA, and MMSE. BDI, PDSS, ADL, and PDQ-39 were rated as low-quality evidence. The pooled results showed significant effects: UPDRS-III (MD: -4.74, 95% CI [-6.78, -2.70], p < 0.00001); TUG(MD: -1.63, 95% CI [-2.41, -0.85], p < 0.0001); BBS(MD:2.80, 95% CI [1.54, 4.06], p < 0.0001); MoCA (MD: 1.93, 95% CI [1.12, 2.74], p < 0.00001); MMSE (MD: 2.80, 95% CI [0.32, 5.29], p = 0.03); BDI (SMD: -0.18, 95% CI [-0.47, 0.12], p = 0.24); PDSS (SMD: -0.31, 95% CI [-0.91, 0.28], p = 0.30); ADL (MD: -0.59, 95% CI [-3.49, 2.31], p = 0.69); and PDQ-39 (MD: -2.85, 95% CI [-6.36, 0.67], p = 0.11).

CONCLUSION: MBE demonstrated statistically significant improvements in motor function and certain cognitive domains in PD patients, suggesting its potential as a beneficial adjunctive non-pharmacological intervention for ameliorating motor symptoms and delaying cognitive decline, whereas evidence for non-motor symptom improvement remains insufficient. Subgroup analysis further indicated a favorable signal of MBE on cognitive function in AD patients; however, the current evidence is preliminary and warrants validation through additional high-quality studies. Given the inherent challenges in implementing double-blinding due to the nature of MBE interventions, coupled with inadequate allocation concealment, the present findings should be interpreted with caution owing to the substantial risks of performance and selection bias.},
}

Humans
*Parkinson Disease/therapy/psychology
*Alzheimer Disease/therapy/psychology
*Mindfulness/methods
*Exercise Therapy/methods
Yoga
Qigong
Tai Ji

@article {pmid42595220,
year = {2026},
author = {Liu, CW and Liu, YM and Li, WJ and Qu, QW and Shan, ZX and Dong, FX and Hou, XQ},
title = {Osthol Ameliorates Alzheimer's Disease-Associated Cognitive Impairment by Targeting the Estrogen-Cholinergic Axis in Age-Stratified Female 3×Tg-AD Mice.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106241},
doi = {10.1016/j.neuint.2026.106241},
pmid = {42595220},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.},
}

@article {pmid42596624,
year = {2026},
author = {Zhang, Z and Tan, H and Shi, F and Dai, J and Ding, W and Li, J and Wang, Y and Yang, R and Xu, X and Chen, C and Xiao, F and Huang, LA and Liu, X and Liao, R and Yan, L},
title = {A Novel Nogo-A Receptor Antagonist Peptide Impedes Alzheimer's Disease Pathology by Nogo-A/NgR/ROCK Signaling Pathway.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {8},
pages = {e71052},
pmid = {42596624},
issn = {1755-5949},
support = {82102690//National Natural Science Foundation of China/ ; 2026A1515011575//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 20211128182437730//Guangdong Provincial Medical Science and Technology Research Fund/ ; 2024A03J0902//2024 Joint between City, University (College) and Enterprise/ ; 21626406//Fundamental Research Funds for the Central Universities/ ; 2025-WJHX-31//Horizontal Research from the Guangdong Provincial Health Economics Association/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism/genetics ; *Signal Transduction/drug effects/physiology ; *rho-Associated Kinases/metabolism ; Mice, Transgenic ; *Nogo Proteins/metabolism/antagonists & inhibitors ; Mice ; Amyloid beta-Peptides/metabolism ; *Nogo Receptor 1/antagonists & inhibitors/metabolism ; Humans ; Peptide Fragments/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; Disease Models, Animal ; tau Proteins/metabolism ; Presenilin-1/genetics ; *Peptides/therapeutic use/pharmacology ; },
abstract = {AIMS: To evaluate the therapeutic effects of NAP2, a novel NgR1 antagonist peptide, on Alzheimer's disease (AD) pathology and to determine whether inhibition of the Nogo-A/NgR1/ROCK signaling axis can ameliorate neurodegenerative alterations in APP/PS1 mice.

METHODS: APP/PS1 transgenic mice received a three-month NAP2 intervention. Cognitive performance was assessed using standard learning and memory tests. Amyloid-β plaque burden, dendritic spine density, tau phosphorylation, and Aβ42 levels were examined by histological and biochemical analyses. Mitochondrial function and downstream ROCK signaling activity were also evaluated.

RESULTS: NAP2 treatment significantly improved cognitive performance in APP/PS1 mice. NAP2 reduced amyloid-β plaque deposition, decreased Aβ42 expression, and increased hippocampal dendritic spine density. Tau hyperphosphorylation was notably attenuated. In addition, NAP2 alleviated Aβ42-induced mitochondrial dysfunction. Mechanistic studies revealed that NAP2 interfered with ROCK signaling downstream of Nogo-A.

CONCLUSION: NAP2 ameliorates multiple AD-related pathological features, an effect accompanied by the inhibition of the Nogo-A/NgR1/ROCK pathway. These findings highlight the therapeutic potential of NAP2 to enhance resilience against Alzheimer's disease pathology.},
}

Animals
*Alzheimer Disease/pathology/drug therapy/metabolism/genetics
*Signal Transduction/drug effects/physiology
*rho-Associated Kinases/metabolism
Mice, Transgenic
*Nogo Proteins/metabolism/antagonists & inhibitors
Mice
Amyloid beta-Peptides/metabolism
*Nogo Receptor 1/antagonists & inhibitors/metabolism
Humans
Peptide Fragments/metabolism
Amyloid beta-Protein Precursor/genetics
Male
Disease Models, Animal
tau Proteins/metabolism
Presenilin-1/genetics
*Peptides/therapeutic use/pharmacology

@article {pmid42596762,
year = {2026},
author = {Mokdad, AH and Dwyer-Lindgren, L and Murray, CJL},
title = {Chronic Disease and Disability in the United States: Trends, Inequities, and Imperatives for Policy Reform.},
journal = {The Milbank quarterly},
volume = {},
number = {},
pages = {},
doi = {10.1111/1468-0009.70109},
pmid = {42596762},
issn = {1468-0009},
abstract = {UNLABELLED: Policy Points Position Universal, High-Quality Education as a Foundational Public Health Strategy. Long-term health and life expectancy in the United States are shaped more by educational attainment than by any other single factor. Disparities in access to early childhood, K-12, and higher education perpetuate cycles of chronic disease, economic hardship, and shortened lifespan, particularly in marginalized communities. Policymakers must recognize education as a critical public health intervention and commit to providing universal access to high-quality education at every stage of life. This transformation requires shifting the focus from mere per-pupil spending toward the national scaling of high-impact instructional models, such as intensive, high-dosage tutoring and adaptive learning. Leveraging generative AI to provide personalized, real-time instruction tailored to individual student needs is essential to bridge the achievement gap at scale. Furthermore, achieving true educational equity requires decoupling school quality from local property taxes, integrating health literacy and nutrition into curricula, and ensuring higher education remains affordable and accessible for all. Transform the Food and Built Environment to Advance National Metabolic Resilience. The structure of America's food system and built environment directly fuels the escalating burden of obesity, diabetes, and related chronic diseases. Federal and state policies must fundamentally shift agricultural subsidies away from calorie-dense, nutrient-poor commodities toward specialty crops and fresh produce. To ensure these healthy choices are the default for every household, the federal government must finalize and enforce mandatory, interpretive front-of-package warning labels for ultra-processed foods. This shift, designed to move beyond the passive Nutrition Facts panel, will provide at-a-glance transparency and incentivize industrywide reformulation. Furthermore, metabolic health must be integrated into the K-12 experience through mandatory daily high-intensity physical activity to improve cardiorespiratory fitness and cognitive performance and minimally processed school meals. Finally, investments in active transportation infrastructure, including pedestrian greenways and safe routes to school, are essential to encourage movement as a default, closing the "convenience gap" that disproportionately burdens low-income and rural Americans. Normalize Chronic Obesity Management. Acknowledging that no nation has successfully reversed the obesity epidemic through behavioral advice alone, the United States must treat obesity as a chronic biological condition rather than a temporary lifestyle lapse. It is imperative that public and private payers guarantee universal, affordable access to evidence-based treatments, including next-generation pharmacotherapies (such as GLP-1 receptor agonists). These clinical strategies must be coupled with a modernized, real-time health data infrastructure to monitor outcomes and ensure equitable access at the neighborhood level.

CONTEXT: Over the past three decades, mortality from leading causes such as cardiovascular disease and cancer has declined in the United States, but the burden of chronic, disabling conditions, including musculoskeletal disorders, mental and substance use disorders, and obesity, has grown or stagnated, widening the gap between total years lived and years lived in good health. These shifts are accompanied by persistent and widening inequities in longevity by geography, race/ethnicity, and socioeconomic status.

METHODS: This analysis draws on the 2023 Global Burden of Disease Study, which estimates mortality, disability, and risk factor burden for 375 diseases and 88 risk factors nationally and at the state level, combined with findings from the US Health Disparities project. The latter uses small-area estimation to evaluate county-level life expectancy and mortality across five racial/ethnic groups and four educational strata, and the "Ten Americas" framework, which stratifies the population by race/ethnicity, geography, and socioeconomic context.

FINDINGS: In 2023, US life expectancy reached 78.5 years and healthy life expectancy 64.5 years, both still below prepandemic 2019 levels, with a persistent 13-14-year gap between life expectancy and healthy life expectancy. Ischemic heart disease remained the leading cause of death, but drug use disorders rose from the 26th to the leading cause of disability, a 562% increase since 1990, while Alzheimer disease and musculoskeletal disorders also climbed in rank. High systolic blood pressure remained the top mortality risk factor despite a large decline, while high body mass index and high fasting plasma glucose burdens grew substantially. State-level disparities widened, with West Virginia and Mississippi trailing Hawaii by wide and increasing margins. Life expectancy gaps by race/ethnicity, education, and place were large and growing, reaching 20.4 years across the "Ten Americas" by 2021, with county-level life expectancy spanning more than 27 years nationally.

CONCLUSIONS: US health trends reflect a shift from fatal to disabling disease, driven substantially by the obesity/metabolic and substance use epidemics, layered onto deep and widening structural inequities by race/ethnicity, place, and education. Reversing these trends requires a multidimensional policy agenda spanning universal, high-quality education; reform of the food and built environment; normalized clinical management of obesity; expanded, integrated substance use and mental health treatment; and modernized, real-time public health data infrastructure.},
}

@article {pmid42597430,
year = {2026},
author = {Powell, WJB and Schindler, SE and Jiménez-Mausbach, M and Oh, IY and Hofmann, A and Snider, BJ and Paczynski, M and Ghoshal, N and Payne, PRO and Lai, AM and Hofford, MR and Gupta, A},
title = {Medical comorbidities of patients receiving amyloid-targeting treatments in a memory clinic.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70445},
pmid = {42597430},
issn = {2352-8729},
abstract = {INTRODUCTION: Trials of amyloid-targeting treatments (ATTs) for early symptomatic Alzheimer's disease (AD) enrolled selected patients with minimal medical comorbidities. We investigated whether real-world memory clinic patients who received ATTs also had fewer comorbidities than the broader clinic population.

METHODS: We extracted data on demographics, comorbidities, and medications from patients who were seen at the Washington University Memory Diagnostic Center from July 1, 2023, through July 1, 2025. We compared the characteristics of patients by biomarker testing status and ATT treatment status.

RESULTS: Of 9938 unique patients, 1948 underwent AD biomarker testing and 335 received ATT infusions (304 lecanemab, 31 donanemab). The patients who underwent biomarker testing or received ATTs were more likely to be White individuals and to have fewer comorbidities than patients who did not undergo testing or receive ATTs.

DISCUSSION: Real-world ATT patients were healthier than the general clinic population and more similar to clinical trial participants.},
}

@article {pmid42597443,
year = {2026},
author = {Tolosa-Tort, P and Okorie, M and Chatterjee, A and Boeriu, AI and Sharma, RU and Andrews, SJ},
title = {Toward personalized medicine in AD/ADRD through genetic-exposome dementia risk assessments.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {70},
pmid = {42597443},
issn = {3005-1940},
abstract = {Genetic-Exposome Dementia Risk Assessments (GEDRA) integrate genomic and environmental risk factors into actionable, patient-centered tools for Alzheimer's disease and related dementias (AD/ADRD). By enabling midlife risk stratification before biomarker or cognitive changes, GEDRA supports personalized medicine through targeted screening, tailored interventions, treatment guidance, and proactive planning. Strategic investment in GEDRA will advance responsible risk communication and translate precision prevention strategies into equitable, clinically meaningful practice.},
}

@article {pmid42597745,
year = {2026},
author = {Martínez-Molina, N and Orte, S and Migliorelli, C and Ribas, V},
title = {Toward precision neuroscience in Alzheimer's disease: the role of multimodal AI.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1903637},
pmid = {42597745},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly understood as a biologically defined and heterogeneous continuum, requiring models that move beyond symptom-based diagnosis toward individualized risk prediction, stratification, and intervention.

OBJECTIVE: This mini-review outlines how precision neuroscience frameworks may support the characterization of AD by integrating multimodal biomarkers, systems biology, systems neurophysiology, digital health markers, and artificial intelligence (AI).

METHODS: We synthesize recent developments across multi-omics profiling, neuroimaging and electrophysiological biomarkers, AI-based speech analysis, and multimodal machine learning approaches, with emphasis on their potential contribution to biologically informed disease staging and personalized clinical decision-making.

RESULTS: Omics and systems biology approaches are expanding the characterization of molecular pathways involved in AD susceptibility, progression, and treatment response. Systems neurophysiology, including multimodal neuroimaging, electrophysiology, and whole-brain modeling, provides complementary markers of large-scale network disruption across the AD continuum. Digital health technologies, particularly AI-based speech analysis, offer scalable and ecologically valid tools for early risk enrichment and longitudinal monitoring. Multimodal AI models further enable the integration of heterogeneous clinical, molecular, imaging, genetic, and behavioral data into probabilistic representations of disease burden and progression. However, clinical translation remains constrained by interpretability, harmonization, validation, fairness, and accessibility challenges.

CONCLUSION: Precision neuroscience offers a promising framework for reconceptualizing AD as a dynamically modeled and biologically stratified disorder. Future progress will depend on robust multimodal datasets, transparent AI methods, longitudinal validation, and equitable implementation strategies capable of supporting early detection, trial enrichment, and personalized prevention or treatment.},
}

@article {pmid42588443,
year = {2026},
author = {Sun, L and Zhu, X and Fan, C and Wang, Y and Chen, Q and Zhang, L and Zhang, Y and Liu, Y},
title = {Pharmacological Effects and Molecular Mechanisms of Lignans in the Treatment of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {15},
pages = {},
pmid = {42588443},
issn = {1420-3049},
support = {82404834//National Natural Science Foundation of China/ ; 2024XJJ-QNCX022, 2024KYYWF-1391//the Youth Science and Technology Innovation Capacity Cultivation Project of Heilongjiang University of Chinese Medicine/ ; CYQN24014//Heilongjiang Chunyan Innovation Team Program/ ; TD2024H002//Heilongjiang Provincial Natural Science Foundation Team Project/ ; LJGXCG2022-096//Heilongjiang Province "Double First-Class" Discipline Collaborative Innovation Achievements Construction Project/ ; },
mesh = {*Lignans/pharmacology/chemistry/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder whose core pathological hallmarks include Aβ aggregation, tau hyperphosphorylation, chronic neuroinflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota dysbiosis. Lignans, a class of naturally occurring polyphenolic dimers widely distributed in medicinal plants and diet, exhibit multi-target neuroprotective effects with low toxicity. This review provides a systematic synthesis of the anti-AD pharmacological mechanisms underlying nine structurally distinct lignan subtypes-dibenzocyclooctadiene, tetrahydrofuran, bisepoxy, benzofuran, and biphenyl types-emphasizing scaffold-dependent structure-activity relationships. Key mechanistic pathways encompass direct inhibition of Aβ aggregation and tau phosphorylation, activation of the Nrf2 antioxidant signaling axis and PI3K/Akt pro-survival pathways, suppression of NF-κB-mediated neuroinflammation, restoration of cholinergic function, protection of mitochondria via SIRT3, inhibition of ferroptosis through Gsk3β/Nrf2/GPX4 signaling, and modulation of the gut-brain axis via microbiota-mediated conversion to enterolactone. This review addresses key pharmacokinetic limitations such as low oral bioavailability, rapid metabolism, and limited brain exposure, alongside strategies including structural modification, brain-targeted delivery systems, and gut microbiota modulation. Despite promising preclinical evidence, clinical translation remains limited. Future research priorities should focus on direct target validation, network pharmacology, optimized formulations, and well-designed clinical trials to develop lignans into next-generation anti-aging and anti-AD therapeutics.},
}

*Lignans/pharmacology/chemistry/therapeutic use
Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use/chemistry
Signal Transduction/drug effects
Oxidative Stress/drug effects

@article {pmid42589213,
year = {2026},
author = {Badawy, AAB and Dawood, S and Clanchy, FIL and Williams, RO and Stone, TW},
title = {Docking Analysis of Drugs Used in the Treatment of Alzheimer's Disease, Using Cell Membrane Receptors and Enzymes of the Kynurenine Pathway: A Pilot Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42589213},
issn = {1422-0067},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Kynurenine/metabolism ; *Molecular Docking Simulation ; Humans ; Pilot Projects ; Cholinesterase Inhibitors/chemistry/pharmacology ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/chemistry ; },
abstract = {Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer's disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to that enzyme, whereas other drugs did not. No docking was observed to the nicotinic acetylcholine receptor (α-7-nAChR). All the drugs tested docked to the kainic acid receptor for glutamate, whereas donepezil, galantamine, tropisetron and N-acetylcysteine docked to the glutamate-NMDA receptor, but none docked to the glutamate-AMPA receptor. Two compounds docked to GABA receptors. Since the kynurenine pathway of tryptophan metabolism has been linked to AlzD, docking was examined with its various enzymes. Docking to tryptophan-2,3-dioxygenase (TDO2), indoleamine-2,3-dioxygenase-1 (IDO1) and 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase was seen with most of the AlzD drugs. Donepezil docked to kynurenine monooxygenase, while rivastigmine, memantine and tropisetron docked to kynurenine aminotransferase-2. There was limited docking to the aryl hydrocarbon receptor and glycolytic enzymes, whereas most drugs docked to phosphoenolpyruvate carboxykinase (PEPCK). Despite their strong docking ability to IDO1 and TDO, none of the compounds tested inhibited their enzyme activity in an assay of kynurenine production. This pilot study highlights the varied pharmacological profile of drugs used in AlzD and suggests that a detailed examination of their functional effects should be considered to assist understanding of their different profiles at on- and off- target sites in human treatment.},
}

*Alzheimer Disease/drug therapy/metabolism
*Kynurenine/metabolism
*Molecular Docking Simulation
Humans
Pilot Projects
Cholinesterase Inhibitors/chemistry/pharmacology
Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/chemistry

@article {pmid42589253,
year = {2026},
author = {Forbes-Hernández, TY and Quiles-Ramírez, C and Giampieri, F and Godos, J and Grosso, G and Rodríguez-Velasco, CL and Xiao, J and Ding, M and Battino, M and Rivas-García, L and Sánchez-González, C},
title = {Integrative Metabolomic Evidence of Bioactive Food-Derived Compounds Targeting Alzheimer's Disease: A Cross-Study Analysis in Caenorhabditis elegans.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42589253},
issn = {1422-0067},
support = {PID2019-106778RB-I00//Government of Spain/ ; Visiting Scholars 2022//Universidad de Granada/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *Metabolomics/methods ; Antioxidants/pharmacology ; Flavonoids/pharmacology ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; *Metabolome ; Cholinesterase Inhibitors/pharmacology ; Disease Models, Animal ; Polyphenols/pharmacology ; },
abstract = {Alzheimer's disease (AD) is a major neurodegenerative condition with limited treatment options. Applications of food-derived products rich in bioactive compounds have emerged as promising strategies, yet comparative evidence across different matrices remains scarce. Here, we present an integrative metabolomic analysis of eleven food extracts previously tested in Caenorhabditis elegans models of AD. By combining chemical fingerprints and functional bioassay data-including oxidative stress resistance, β-amyloid-induced paralysis, and tau-associated locomotion-we employed multivariate statistics to uncover common patterns and correlations. Principal Component Analysis, PLS-DA, and hierarchical clustering revealed distinct groupings of extracts based on metabolite profiles and neuroprotective effects. Polyphenols, flavonoids, and iridoids were consistently associated with beneficial outcomes, while antioxidant capacity and acetylcholinesterase inhibition emerged as key functional traits. Correlation heatmaps highlighted extract-specific strengths, suggesting potential for rational combinations targeting complementary bioactivities. This work underscores the value of integrating metabolomics and functional biology to inform the design of food-based interventions for neurodegenerative diseases, paving the way for evidence-based innovation in brain health.},
}

Animals
*Caenorhabditis elegans/metabolism/drug effects
*Alzheimer Disease/metabolism/drug therapy
*Metabolomics/methods
Antioxidants/pharmacology
Flavonoids/pharmacology
Oxidative Stress/drug effects
Neuroprotective Agents/pharmacology
Amyloid beta-Peptides/metabolism
*Metabolome
Cholinesterase Inhibitors/pharmacology
Disease Models, Animal
Polyphenols/pharmacology

@article {pmid42589276,
year = {2026},
author = {Kanagawa, H and Kawahara, A and Mikawa, N and Sugihara, K and Ueda, M and Nitta, A and Egi, M and Oda, R and Nonaka, S and Tozaki-Saitoh, H and Oda, K and Nakanishi, H},
title = {Candidalysin Inhibits Porphyromonas gingivalis Lipoprotein-Induced IL-1β Production in BV-2 Microglia via Hydrophobic Microbial Interactions.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42589276},
issn = {1422-0067},
support = {JP24K09808 (S.N.) and JP24K09787 (K.O.).//JSPS KAKENHI/ ; },
mesh = {*Interleukin-1beta/metabolism/biosynthesis ; *Microglia/metabolism/drug effects/microbiology ; *Porphyromonas gingivalis/metabolism/pathogenicity ; Hydrophobic and Hydrophilic Interactions ; Animals ; *Lipoproteins/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; NF-kappa B/metabolism ; Cell Line ; },
abstract = {In postmortem Alzheimer's disease (AD) brains, Porphyromonas gingivalis (Pg), a major periodontal pathogen, and Candida albicans, one of the most common fungal pathogens, have been detected. Although it is important to better understand the effects of their co-infection in the brain for elucidating the pathogenesis of AD, little is known about the neuropathological significance of such co-infection. In the present study, we aimed to elucidate the effects of co-exposure to virulence factors derived from Pg and C. albicans on microglial inflammatory responses. We demonstrated, for the first time, that both candidalysin dissolved in dimethyl sulfoxide (CLd) and water (CLw) significantly suppressed Pg lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) production by 35-60% and nuclear factor-κB (NF-κB) activation by 20-40%. It should be noted that contaminating Pg outer membrane lipoproteins in Pg LPS were mainly responsible for IL-1β production. To examine the possible hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL, we used 8-anilino-1-naphthalenesulfonic acid sodium salt (ANS-Na), which can be excited to emit fluorescence by binding of hydrophobic molecules. The mean fluorescence intensity of ANS-Na was significantly reduced by approximately 26% following co-treatment with CLw and Pg LPS compared with CLw alone. Furthermore, we generated a mutant form of CL with reduced hydrophobicity (GRAVY index: 1.106 vs. 0.874) while preserving its predicted structural properties. This mutant CLd no longer inhibited Pg LPS-induced IL-1β production. Taken together, these findings indicate that hydrophobic interactions between lipoproteins contaminating the Pg LPS preparation and CL mediate the inhibitory effect of CL on Pg LPS-induced inflammatory responses. The present findings suggest that interactions between polymicrobial virulence factors in the brain may modulate microglia-mediated inflammatory responses during AD progression.},
}

*Interleukin-1beta/metabolism/biosynthesis
*Microglia/metabolism/drug effects/microbiology
*Porphyromonas gingivalis/metabolism/pathogenicity
Hydrophobic and Hydrophilic Interactions
Animals
*Lipoproteins/metabolism
Lipopolysaccharides/pharmacology
Mice
NF-kappa B/metabolism
Cell Line

@article {pmid42589569,
year = {2026},
author = {Tan, CL and Zheng, XM and Zhu, YF and Xiong, QQ and Li, H and Meng, XL},
title = {CellSwarm-AD: A Multi-Scale Agent-Based Framework for Virtual Alzheimer's Disease Trials.},
journal = {International journal of molecular sciences},
volume = {27},
number = {15},
pages = {},
pmid = {42589569},
issn = {1422-0067},
support = {32400068//National Natural Science Foundation of China/ ; 2025T180738//China Postdoctoral Science Foundation/ ; 2024M750284//China Postdoctoral Science Foundation/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Computer Simulation ; Amyloid beta-Peptides/metabolism ; Donepezil/therapeutic use/pharmacokinetics ; Memantine/therapeutic use/pharmacokinetics ; },
abstract = {Computational models of Alzheimer's disease (AD) rarely connect cellular heterogeneity, spatial tissue organization, pathology cascades, and pharmacological intervention within one auditable workflow. We present CellSwarm-AD, a four-layer framework comprising five cell agent classes, a spatial Aβ diffusion environment, an Aβ-Ca[2+]-tau-NF-κB-viability cascade with repository PK/PD models, and an optional experiment orchestration interface. Layer 3 was demonstrated with reproducible prompt templates and deterministic mock outputs; no live large language model was used to generate or modify the quantitative simulation outputs or statistical results. In a prespecified 78-week virtual trial (n = 200 per arm), patient-level repeated measurements were analyzed with Gaussian generalized estimating equations. Week-78 mean (SEM) MMSE-like changes were -1.747 (0.071) for the placebo, -1.368 (0.076) for lecanemab, -1.428 (0.067) for donepezil, and -1.369 (0.065) for independently simulated donepezil plus memantine. The corresponding single-trial Cohen's d values versus the placebo were 0.395, 0.354, and 0.426. Across 20 independent n = 200-per-arm trials, the mean d values were 0.337, 0.359, and 0.326, respectively; replicates were not pooled. Ablation removed most of the treatment contrast when PK/PD was disabled, and fixed-domain grid testing showed decreasing relative L2 error from 6.20% (100 × 100) to 1.49% (200 × 200) against a 400 × 400 reference. These results establish a reproducible proof-of-concept while identifying calibration dependence, weak cross-layer coupling, and the absence of individual-level external validation as current limitations.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Computer Simulation
Amyloid beta-Peptides/metabolism
Donepezil/therapeutic use/pharmacokinetics
Memantine/therapeutic use/pharmacokinetics

@article {pmid42590850,
year = {2026},
author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M},
title = {Long-term safety and immunogenicity of ABvac40 active immunotherapy in mild cognitive impairment and very mild Alzheimer's disease: Results from AB1601 phase 2 extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {8},
pages = {e71746},
pmid = {42590850},
issn = {1552-5279},
support = {//Araclon Biotech-Grifols./ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy ; Female ; Male ; Amyloid beta-Peptides/immunology ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods/adverse effects ; Peptide Fragments/immunology ; Double-Blind Method ; Treatment Outcome ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Aged, 80 and over ; },
abstract = {INTRODUCTION: ABvac40 is an active immunotherapy targeting Aβ40, the main component of cerebrovascular deposition in Alzheimer's disease (AD). A 24-month randomized, placebo-controlled phase 2 study (Part A) showed favorable safety and robust immunogenicity, with exploratory signals of clinical efficacy. Here, we report results from Part B, an 18-month extension evaluating long-term safety and immunological memory.

METHODS: Participants treated with ABvac40 in Part A received placebo plus a delayed booster, whereas previous placebo participants received ABvac40. Exploratory endpoints included safety, tolerability, and immunogenicity.

RESULTS: Seventy-seven participants entered Part B. Treatment-emergent adverse events (TEAEs) occurred in 75.0% of participants in placebo + booster group and 81.1% in ABvac40 group; serious TEAEs were 5.0% and 16.2%, respectively. No ARIA-E or meningoencephalomyelitis were observed, with one ARIA-H event. ABvac40 induced robust antibody responses following delayed booster, with detectable anti-Aβ40 antibodies in CSF.

DISCUSSION: ABvac40 showed favorable long-term safety and durable immunogenicity, supporting further clinical development.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT03461276, registered March 2, 2018. EudraCT: 2016-004352-30, registered March 10, 2017.},
}

Humans
*Alzheimer Disease/therapy/immunology/drug therapy
Female
Male
Amyloid beta-Peptides/immunology
Aged
*Cognitive Dysfunction/therapy/immunology/drug therapy
*Immunotherapy, Active/methods/adverse effects
Peptide Fragments/immunology
Double-Blind Method
Treatment Outcome
*Alzheimer Vaccines/therapeutic use/adverse effects
Aged, 80 and over

@article {pmid42591325,
year = {2026},
author = {Shin, J and Suh, SI and Park, YJ and Lee, S and Kang, J and Lee, ES and Jung, HN and Ryoo, I and Lee, S and Eo, JS and Oh, K and Koh, SB and Kang, SH},
title = {Real-world implementation of lecanemab in Korean patients at a tertiary memory clinic: Safety, ARIA risk, and early treatment patterns.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70447},
pmid = {42591325},
issn = {2352-8729},
abstract = {INTRODUCTION: Lecanemab has demonstrated clinical efficacy in early Alzheimer's disease (AD), but real-world data remain limited, particularly in Asian populations.

METHODS: We prospectively enrolled 127 patients across the AD continuum who initiated lecanemab at a tertiary memory clinic in Korea. Infusion-related reactions (IRRs), amyloid-related imaging abnormalities (ARIAs), and cognitive outcomes were evaluated through clinical assessments, serial magnetic resonance imaging (MRI), and longitudinal Mini-Mental State Examination (MMSE) follow-up.

RESULTS: Among 127 patients, 102 completed at least five infusions with follow-up MRI. IRRs occurred in 27 (21.3%) patients, primarily during the first infusion. ARIAs occurred in 9 of 102 (8.8%), including ARIAs with edema in 4 (3.9%) and ARIA with hemorrhage in 7 (6.9%); most events were mild or asymptomatic. Higher microbleed burden and white matter hyperintensity were associated with increased ARIA risk. MMSE scores remained stable over 6 months.

DISCUSSION: In this prospective Korean cohort, lecanemab was generally well tolerated. Longer term controlled studies are needed to clarify cognitive outcomes.},
}

@article {pmid42593033,
year = {2026},
author = {Değirmenci, S and Tırın, H and Arıkan, E and Andiç, K and Sezgin, E},
title = {Red cell distribution width and modified 5-item frailty index to predict short-term mortality in patients undergoing surgery for hip fracture.},
journal = {Ulusal travma ve acil cerrahi dergisi = Turkish journal of trauma & emergency surgery : TJTES},
volume = {32},
number = {8},
pages = {998-1007},
doi = {10.14744/tjtes.2026.20432},
pmid = {42593033},
issn = {1307-7945},
mesh = {Humans ; Female ; *Hip Fractures/surgery/mortality/blood ; Aged, 80 and over ; Male ; *Erythrocyte Indices ; Aged ; *Frailty/mortality ; Intensive Care Units/statistics & numerical data ; Hospital Mortality ; Prognosis ; Turkey ; },
abstract = {BACKGROUND: Hip fractures (HFs), which are common in the geriatric population and have a high mortality rate, are among the pathologies frequently encountered in emergency departments (EDs). The aim of this study was to investigate the prognostic value of red cell distribution width (RDW) and modified 5-item frailty index (mFI-5) scores in the prediction of short-term mortality and intensive care unit (ICU) admission in patients with HFs.

METHODS: Patients who presented to the ED due to HF between January 01, 2019, and December 31, 2023, were evaluated. Patients who underwent surgery for femoral neck, intertrochanteric, or subtrochanteric fractures were included in the study. Baseline demographics (age and sex), comorbidities, ICU admission status, and in-hospital and 30-day mortality rates were recorded. Univariate and multivariable logistic regression analyses were performed to identify independent predictors of ICU admission and 30-day mortality.

RESULTS: A total of 413 patients undergoing surgical treatment for HFs were included. The mean age of the patients was 80±11 years, and 271 (65.6%) were female. ICU admission was required for 43 patients (10%), while in-hospital and 30-day mortality rates were 7% (n=30) and 9.9% (n=41), respectively. Multivariable logistic regression analysis identified RDW as an independent predictor of both ICU admission (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05-1.41; p=0.009) and 30-day mortality (OR 1.20, 95% CI 1.03-1.39; p=0.016). Atrial fibrillation (AF) and Alzheimer's disease were also identified as independent predictors of ICU admission, while AF and age independently predicted 30-day mortality. The mFI-5 score did not reach statistical significance in univariate analysis for either outcome. A predictive model incorporating RDW and other covariates achieved area under the curve values of 0.74 for ICU admission and 0.70 for 30-day mortality.

CONCLUSION: RDW emerged as an independent predictor of ICU admission and 30-day mortality in surgically managed HF patients, with improved discriminatory performance when integrated into a multiparametric model. Advanced age, Alzheimer's disease, and AF further contribute to increased risk and should be closely monitored in clinical management. These findings support the incor-poration of RDW into routine emergency risk stratification for this vulnerable population.},
}

Humans
Female
*Hip Fractures/surgery/mortality/blood
Aged, 80 and over
Male
*Erythrocyte Indices
Aged
*Frailty/mortality
Intensive Care Units/statistics & numerical data
Hospital Mortality
Prognosis
Turkey

@article {pmid42593551,
year = {2026},
author = {Arriagada, J and Lantadilla, M and Lobos, P and Paz, AA and Herrera, EA and Muñoz, P and Paula-Lima, A},
title = {Metformin Enhances Antioxidant Defenses and Limits Lipid Peroxidation Through the Modulation of Nrf2/KEAP1 Pathway in Hippocampal Neurons Exposed to Amyloid-β Oligomers.},
journal = {Neurotoxicity research},
volume = {44},
number = {4},
pages = {},
pmid = {42593551},
issn = {1476-3524},
support = {Doctorate National Scholarship No. 2123 0993//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1241502//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grants No. 1251980//Agencia Nacional de Investigación y Desarrollo/ ; FONDECYT Regular Grant No. 1261188//Agencia Nacional de Investigación y Desarrollo/ ; Universidad de Chile RS0925//Universidad de Chile/ ; Universidad de Chile RS0925//Universidad de Chile/ ; INACH 16-21//Institut chilien de l'Antarctique/ ; },
mesh = {Animals ; *NF-E2-Related Factor 2/metabolism ; *Amyloid beta-Peptides/toxicity ; *Metformin/pharmacology ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Hippocampus/drug effects/metabolism ; *Neurons/drug effects/metabolism ; *Lipid Peroxidation/drug effects/physiology ; Signal Transduction/drug effects ; *Antioxidants/metabolism/pharmacology ; Cells, Cultured ; Rats ; Peptide Fragments/toxicity ; Oxidative Stress/drug effects ; },
abstract = {Oxidative stress is an early and important feature of Alzheimer's disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.},
}

Animals
*NF-E2-Related Factor 2/metabolism
*Amyloid beta-Peptides/toxicity
*Metformin/pharmacology
*Kelch-Like ECH-Associated Protein 1/metabolism
*Hippocampus/drug effects/metabolism
*Neurons/drug effects/metabolism
*Lipid Peroxidation/drug effects/physiology
Signal Transduction/drug effects
*Antioxidants/metabolism/pharmacology
Cells, Cultured
Rats
Peptide Fragments/toxicity
Oxidative Stress/drug effects

@article {pmid42594210,
year = {2026},
author = {Reardon, S},
title = {Tau can wreak havoc in brain cells' energy factories.},
journal = {Science (New York, N.Y.)},
volume = {393},
number = {6812},
pages = {651},
doi = {10.1126/science.ael4194},
pmid = {42594210},
issn = {1095-9203},
mesh = {*Mitochondria/metabolism ; Humans ; *tau Proteins/metabolism ; *Brain/metabolism/cytology ; *Alzheimer Disease/metabolism/drug therapy ; Animals ; *Energy Metabolism ; *Neurons/metabolism ; },
abstract = {Study of mitochondria suggests new treatment strategy for Alzheimer's and other diseases.},
}

*Mitochondria/metabolism
Humans
*tau Proteins/metabolism
*Brain/metabolism/cytology
*Alzheimer Disease/metabolism/drug therapy
Animals
*Energy Metabolism
*Neurons/metabolism

@article {pmid42594414,
year = {2026},
author = {Dinnerstein, E},
title = {The missing improvers: Tau pathology, neuroplasticity, and the case for tau-informed patient selection before amyloid immunotherapy.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {9},
pages = {100653},
doi = {10.1016/j.tjpad.2026.100653},
pmid = {42594414},
issn = {2426-0266},
abstract = {Amyloid immunotherapy with lecanemab and donanemab has been approved on the basis of statistically significant slowing of cognitive and functional decline in early Alzheimer's disease (1,2). Yet clinicians treating individual patients face the everyday challenge of estimating whether a given patient is declining at the rate that would be expected for them, and whether their trajectory reflects a response to treatment. I argue that this difficulty arises in large part because the field cannot yet routinely stratify patients by tau pathology before treatment, even though tau burden is among the strongest available predictors of both the rate of progression and the magnitude of response to amyloid-targeting therapy. Post-hoc and open-label analyses of the Clarity AD and TRAILBLAZER-ALZ 2 programmes suggest that patients with absent, low, or medium tau burden may constitute a biologically distinct group in whom amyloid clearance is most likely to permit clinical stabilization or measurable functional gain. These observations remain hypotheses, generated largely from subgroup, open-label, and biomarker data rather than from prospective trials designed to test them I propose that tau status should be given strong consideration in patient selection, that tau-guided selection should be evaluated prospectively, and that the access, reimbursement, and standardization barriers to tau positron emission tomography (PET) - together with the promise of scalable plasma tau biomarkers - be addressed deliberately as the field moves toward tau-informed treatment. One tau PET tracer is currently approved by the US Food and Drug Administration, and a regulatory decision on a second is anticipated in 2026.},
}

@article {pmid42594906,
year = {2026},
author = {Koychev, I and Holman, RR},
title = {Semaglutide treatment fails but might prevent Alzheimer's disease.},
journal = {Lancet (London, England)},
volume = {408},
number = {10555},
pages = {602-603},
doi = {10.1016/S0140-6736(26)01647-8},
pmid = {42594906},
issn = {1474-547X},
}

@article {pmid42579441,
year = {2026},
author = {Sun, F and Liu, Y and Zhou, Q and Hu, Q and Wang, W and Xiao, Y and Su, J and Liu, G and Sun, M and Chen, L and Li, H and Yang, Y and Wang, JZ},
title = {A Small-Molecule DEPTAC Rescues Cognitive Deficits by Targeted Dephosphorylation of Pathological Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e77088},
pmid = {42579441},
issn = {2198-3844},
support = {82571635//National Natural Science Foundation of China/ ; 82230041//National Natural Science Foundation of China/ ; 82371436//National Natural Science Foundation of China/ ; YCJJ20252412//Fundamental Research Funds for the Central Universities/ ; 241111310400//Key R&D Program of Henan Province/ ; },
abstract = {Accumulation of hyperphosphorylated Tau (p-Tau) is a central driver of neurodegeneration in Alzheimer's disease (AD). Addressing the limitations of current therapeutics, we developed TP2, a small-molecule DEPhosphorylation-TArgeting Chimera (DEPTAC). TP2 is engineered to physically tether endogenous PP2A to Tau, facilitating targeted dephosphorylation. Mechanistically, TP2 induces ternary complex formation and potently reduces p-Tau in neurons. Systemic administration of TP2 in distinct tauopathy mouse models (P301L and AAV-hTau-N368) significantly lowered brain p-Tau levels, oligomers, and neurofibrillary tangles without altering global PP2A activity. Crucially, by rebalancing the phosphorylation of Tau, TP2 restored Tau's physiological function, as evidenced by the preservation of neuronal morphology, synaptic integrity, and microtubule stability. TP2 also ameliorated the dysregulated neuroimmune microenvironment. Consequently, TP2 treatment robustly reversed cognitive deficits in multiple behavioral paradigms. These findings establish TP2 as a promising therapeutic candidate that targets upstream pathological phosphorylation to halt neurodegeneration and restore cognitive function.},
}

@article {pmid42580389,
year = {2026},
author = {Bu, J and Nie, X and Luo, H and Wang, J and Jiang, D and Xu, N and Zhuang, P and Zhang, Y and Yin, Q},
title = {Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108383},
doi = {10.1016/j.phrs.2026.108383},
pmid = {42580389},
issn = {1096-1186},
abstract = {Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid42580438,
year = {2026},
author = {Silva, AC},
title = {Current Clinical Evidence on Nose-to-Brain Drug Delivery.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104765},
doi = {10.1016/j.drudis.2026.104765},
pmid = {42580438},
issn = {1878-5832},
abstract = {Intranasal delivery is increasingly recognised as a promising strategy for direct drug transport to the brain via the nose-to-brain pathway, bypassing the blood-brain barrier and improving therapeutic efficacy. This approach has shown potential in the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, and acute psychiatric conditions, as well as in emergencies such as anxiety attacks and migraine episodes. Recent clinical studies investigating intranasal formulations of rivastigmine, insulin, and olanzapine, among other drugs, have provided encouraging evidence supporting the clinical translation of this delivery strategy. In addition, FDA-approved intranasal products indicated for central nervous system disorders, including diazepam and midazolam for seizure management, and triptans for migraine, demonstrate the growing clinical relevance of intranasal drug delivery. Both preclinical and clinical studies have reported encouraging outcomes, particularly when intranasal delivery is combined with nanoformulations and specialised delivery devices designed to enhance olfactory deposition. Intranasal administration is non-invasive, painless, and may improve patient adherence while enhancing brain bioavailability. Nevertheless, further well-designed clinical studies are required to establish the long-term safety, efficacy, and clinical applicability of this delivery strategy.},
}

@article {pmid42581224,
year = {2026},
author = {Stefano, GB and Esch, T},
title = {Microbiome-Inflammation-Mitochondria Coupling in Neurodegeneration and Depression: An Integrative Opinion.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42581224},
issn = {1559-1182},
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Inflammation/pathology/microbiology/metabolism ; *Depression/microbiology/metabolism/pathology ; *Neurodegenerative Diseases/microbiology/pathology/metabolism ; *Microbiota ; *Gastrointestinal Microbiome/physiology ; *Nerve Degeneration/pathology ; },
abstract = {There is increasing evidence that gut microbiome dysbiosis, systemic inflammation, and mitochondrial dysfunction interact in ways that influence psychiatric and neurodegenerative disease vulnerability. Recent findings indicate that microbial signaling, inflammatory activation, and mitochondrial stress responses form dynamic bidirectional networks that may influence neurotransmission, neuroplasticity, metabolism, and behavior. This integrative opinion article distinguishes major depressive disorder (MDD), Parkinson's disease (PD), and Alzheimer's disease (AD) as mechanistically distinct disorders while proposing that they may share overlapping upstream modulatory pathways involving inflammation, microbial dysregulation, and mitochondrial dysfunction. Importantly, the microbiome-inflammation-mitochondria axis is presented as a disease-modifying and vulnerability-associated framework rather than a singular unifying etiology. Current limitations including reverse causation, microbiome heterogeneity, and differences in treatment responsiveness are also discussed.},
}

Humans
*Mitochondria/metabolism/pathology
Animals
*Inflammation/pathology/microbiology/metabolism
*Depression/microbiology/metabolism/pathology
*Neurodegenerative Diseases/microbiology/pathology/metabolism
*Microbiota
*Gastrointestinal Microbiome/physiology
*Nerve Degeneration/pathology

@article {pmid42581666,
year = {2026},
author = {Williams, A and Reddy, ABS and Velayudhan, L},
title = {A Systematic Review of Effects of Cholinesterase Inhibitors and Memantine on Cognitive Domains in Alzheimer's Disease.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261470005},
doi = {10.1177/08919887261470005},
pmid = {42581666},
issn = {1552-5708},
abstract = {BackgroundAlzheimer's Disease (AD) is characterised by progressive cognitive decline. Cholinesterase inhibitors (ChEI) (donepezil, rivastigmine and galantamine) and memantine have been the mainstay treatment and have showed their effectiveness on total cognitive scores, but their effects on individual cognitive domains remain unclear. This systematic review examined their impact on individual cognitive domains.MethodPubMed, Cochrane, MEDLINE, Web of Science and PsycINFO were searched (1st January 1999 - 31st March 2025) for studies evaluating the effects of ChEI and memantine on cognitive domains using standardised cognitive scales in individuals with AD. The review followed PRISMA guidelines. Risk of bias was assessed using the Cochrane ROB1 tool and a narrative synthesis was used to report the main findings.ResultsSixteen studies were included. Rivastigmine demonstrated dose-dependent benefits across memory, language, and praxis domains, with higher-doses generally producing less cognitive decline and greater improvements than lower-dose patches or capsules. Donepezil yielded benefits in language, praxis, and visuospatial abilities. Galantamine showed significant improvements in memory, praxis, visuospatial function, and language, and was superior to donepezil in language in one comparative study. Memantine demonstrated benefits across memory, language, praxis, attention, and visuospatial domains, both as monotherapy and as an adjunct to donepezil, with adjunct therapy producing sustained improvements in language and praxis. Overall, higher treatment doses were consistently associated with greater preservation of cognitive function across domains.DiscussionChEIs and memantine provide domain-specific cognitive benefits beyond global cognitive improvement. Future studies should examine whether treatment tailored to domain-specific deficits improves patient outcome.PROSPEROCRD42024493998.},
}

@article {pmid42582267,
year = {2026},
author = {Winzell, F and Arvidsson, I and Overgaard, NC and Heyden, A and Åström, K and Karlsson, L and Vogel, JW and Hansson, O and Mattsson-Carlgren, N and , },
title = {Benchmarking privacy and utility in synthetic tabular cohorts for Alzheimer's disease research.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {3},
pages = {e70430},
pmid = {42582267},
issn = {2352-8729},
abstract = {INTRODUCTION: The scarcity of large, clinically relevant cohorts is becoming a bottleneck in Alzheimer's disease (AD) research, as their sensitive nature makes open data sharing difficult. Privacy-preserving synthetic datasets generated with machine learning may help address this challenge.

METHODS: We compared five frameworks for generating synthetic tabular data from the Alzheimer's Disease Neuroimaging Initiative and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease cohorts, with a set of empirical privacy and utility metrics. Two of the methods, DataSynthesizer and TableDiffusion, provide ε -differential privacy guarantees.

RESULTS: Methods with differential privacy achieved high privacy ratings but low levels of utility. Deep learning methods like Tabular Prior-data Fitted Network (TabPFN) and Conditional Generative Adversarial Network (CTGAN) also showed high privacy with limited utility. In contrast, non-private DataSynthesizer and Synthpop offered higher utility at a cost of lower privacy.

DISCUSSION: The evaluated methods demonstrated a clear trade-off between privacy and utility. High privacy was generally associated with insufficient utility, highlighting the need for further research into synthetic data generation for AD.},
}

@article {pmid42583026,
year = {2026},
author = {Erdal, M and Arı, A and Emekli, AS and Yılmaz, NÇ and Kürtüncü, M},
title = {Clinical Use of Interleukin-6 Blockade in Neuroimmunological Disorders.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {482-494},
pmid = {42583026},
issn = {1300-0667},
abstract = {Interleukin-6 (IL-6) is a multifunctional cytokine that plays a critical role in immune regulation, host defense, and tissue repair. Within the central nervous system (CNS), IL-6 contributes to both neuroprotection and neuroinflammation, depending on the signaling pathway involved; classic signaling, trans-signaling, or trans-presentation. Dysregulation of IL-6, particularly through sustained overexpression, disrupts the blood-brain barrier (BBB) integrity, promotes glial activation, and amplifies chronic inflammation, thereby contributing to the pathophysiology of numerous neurological disorders. This review aims to evaluate the role of IL-6 in neuroinflammatory processes and its clinical implications across a spectrum of neurological diseases. It focuses on the therapeutic potential and safety profile of IL-6 inhibitors, particularly tocilizumab and satralizumab. Key conditions discussed include neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), autoimmune encephalitis (AE), neuro-Behçet's disease (NBD), myasthenia gravis (MG), epilepsy, multiple sclerosis (MS), and Alzheimer's disease (AD). Clinical trials have demonstrated the efficacy of IL-6 receptor blockade in reducing relapse rates in NMOSD, leading to regulatory approvals. Promising off-label results have also been reported in treatment-resistant cases of MOGAD, epilepsy, and autoimmune conditions. However, IL-6 inhibition carries risks such as serious infections and paradoxical inflammatory reactions. Targeting the IL-6 pathway represents a significant advancement in neuroimmunology, offering new therapeutic opportunities for otherwise refractory conditions. Future research should focus on large-scale randomized controlled trials and the development of IL-6 inhibitors capable of crossing the BBB to enhance CNS-specific efficacy. Cost-related accessibility also remains a major challenge for broader clinical application.},
}

@article {pmid42583837,
year = {2026},
author = {Zhu, N and Xu, H and Garcia-Ptacek, S and Mitra, S and Eriksdotter, M},
title = {Oral anticoagulants, cognition, and clinical outcomes in atrial fibrillation and Alzheimer's disease: a Swedish nationwide study.},
journal = {European heart journal},
volume = {},
number = {},
pages = {},
doi = {10.1093/eurheartj/ehag584},
pmid = {42583837},
issn = {1522-9645},
support = {FoUI-1002840//Center for Innovative Medicine/ ; AF-1032116//Swedish Alzheimer's Foundation/ ; M24-0221//Åke Wiberg Foundation/ ; 2022-01428//Swedish Research Council/ ; 2022-01425//Swedish Research Council/ ; 2024-03599//Swedish Research Council/ ; M-2024-2526//Petrus and Augusta Hedlund Foundation/ ; 2024-1370//Magnus Bergvall Foundation/ ; //Swedish Kidney Foundation/ ; //Karolinska Institutet internal funds/ ; //Karolinska Institutet/ ; //Emil and Wera Cornell Foundation/ ; //Swedish Dementia Foundation/ ; //Stockholm County Council and Karolinska Institutet/ ; //New Innovative Roads Call/ ; //Leif Lundblad/ ; //Loo and Hans Osterman Foundation/ ; //Gun and Bertil Stohne Foundation/ ; //Swedish Dementia Foundation/ ; //Tore Nilson Foundation/ ; //Gamla Tjänarinnor Foundation/ ; //Lindhés Advokatbyrå Foundation/ ; //Mats Paulsson Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 2021-02680//PREDEM/ ; },
abstract = {BACKGROUND AND AIMS: Use of non-vitamin K oral anticoagulants (NOACs) is associated with reduced dementia risk in patients with atrial fibrillation (AF), but their impact on cognitive function and clinical outcomes in AF patients with Alzheimer's disease (AD) remains unclear.

METHODS: Based on the Swedish Registry for Cognitive/Dementia Disorders, individuals with incident AD during May 2007-December 2020 and pre-existing AF were identified. Anticoagulant use at baseline was categorized as non-use, warfarin, or NOACs. Inverse probability of treatment weighting was employed to balance covariates. Mixed-effects models were used to assess the association between anticoagulant use and cognitive decline measured by the Mini-Mental State Examination (MMSE). Cox proportional hazards models were used to examine risks of all-cause mortality, ischaemic stroke/systemic embolism, major bleeding, and fracture.

RESULTS: Among 7308 eligible individuals (3341 non-users, 2277 warfarin users, and 1690 NOAC users), NOAC users exhibited significantly slower cognitive decline compared to non-users (difference in MMSE scores β = 0.23 points/year, 95% confidence interval [CI] 0.11-0.36) and warfarin users (β = 0.21 points/year, 95% CI 0.10-0.33). Compared to non-use of anticoagulants, NOAC use was associated with significantly lower rates of mortality (hazard ratio [HR] 0.81; 95% CI 0.72-0.91), ischaemic stroke/systemic embolism (HR 0.66; 95% CI 0.53-0.82), and fracture (HR 0.79; 95% CI 0.64-0.97), without an increased rate of major bleeding (HR 1.05; 95% CI 0.84-1.32); in contrast, warfarin use was associated with significantly lower rates of mortality (HR 0.88; 95% CI 0.80-0.97) and ischaemic stroke/systemic embolism (HR 0.85; 95% CI 0.72-1.00), but a higher rate of major bleeding (HR 1.31; 95% CI 1.09-1.56). Compared to warfarin, NOAC use was associated with lower rates of ischaemic stroke/systemic embolism (HR 0.78; 95% CI 0.62-0.98) and major bleeding (HR 0.80; 95% CI 0.64-1.01), and non-significant reductions in mortality and fracture.

CONCLUSIONS: In patients with AF and AD, NOAC use was associated with modestly slower cognitive decline and more favourable effectiveness and safety profiles, compared to warfarin or no anticoagulation.},
}

@article {pmid42584743,
year = {2026},
author = {Wani, OH and Dhaka, P and Pinky, and Choudhary, SS and Wani, AA and Iqbal, A and Parvez, S and Dar, TA},
title = {Majoon-e-Boolis as a neurotherapeutic agent: cognitive and neuronal restoration in alzheimer's disease model.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42584743},
issn = {1573-7365},
support = {3-67/2022-CCRUM/Tech//Central Council for Research in Unani Medicine/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Rats ; Oxidative Stress/drug effects ; Male ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Amyloid beta-Peptides ; *Cognition/drug effects ; *Neurons/drug effects/metabolism ; Antioxidants/pharmacology/therapeutic use ; Peptide Fragments ; Rats, Wistar ; },
abstract = {Majoon-e-Boolis (MB), a traditional Unani formulation, has been used for neurological conditions; however, its molecular mechanism remains largely unexplored. The current study was designed to explore the novel mechanistic insights between antioxidant activity, anti-inflammatory effects, dopaminergic support and anti-aggregation properties of the formulation for modulating the pathogenesis of Alzheimer's Disease (AD). Behavioral deficits were studied via Novel Object Recognition, Elevated Plus Maze and Open Field Test. In addition, the study looked at the immunohistochemistry of superoxide dismutase 2, tumor necrosis factor-alpha, tyrosine hydroxylase and α-synuclein (α-Syn) against Aβ1-42-induced AD model. Additionally, histopathological alterations were also performed against the AD model. The observed findings demonstrated that MB treatment in Aβ1-42-induced AD in rat models significantly improved their cognitive impairments and alleviated anti-anxiety behaviour with enhanced locomotor activity. Moreover, MB induced significant reduction in oxidative stress and neuroinflammation with enhanced dopaminergic neuronal activity. GC-MS analysis of MB revealed the presence of bioactive phytochemicals such as thiophene, guanidinopropionic acid, 5-hydroxymethylfurfural etc. The findings underscore the potential of MB as a promising therapeutic agent in mitigating the multifaceted pathology of Aβ1-42-induced AD in a rat model by exerting its neuroprotective effects, cognition restoration and overall maintenance of neuronal architecture through a combination of antioxidant, anti-inflammatory and anti-aggregation mechanisms, making it a multifaceted therapeutic candidate for AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
Rats
Oxidative Stress/drug effects
Male
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Amyloid beta-Peptides
*Cognition/drug effects
*Neurons/drug effects/metabolism
Antioxidants/pharmacology/therapeutic use
Peptide Fragments
Rats, Wistar